Bioluminescent CXCL12 Fusion Protein

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\pard\li9200\ri0\sl-186\slmult0 \fs16\cf1\f0\charscalex100 {Research Reports}\pa
r\pard\li360\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li360\ri0\sl-680\slmult0 \fs4
6\cf2\f0\charscalex100 {Bioluminescent CXCL12 fusion protein for cellular}\par\p
ard\li360\ri0\sl-546\slmult0 \fs46\cf2\f0\charscalex100 { studies of CXCR4 and C
XCR7}\par\pard\li360\ri0\sl-346\slmult0 \fs24\cf0\f0\charscalex100 {Kathryn E. L
uker}\fs16\cf0\f0\charscalex100 {1}\fs24\cf0\f0\charscalex100 {, Mudit Gupta}\fs
16\cf0\f0\charscalex100 {1}\fs24\cf0\f0\charscalex100 {, and Gary D. Luker}\fs16
\cf0\f0\charscalex100 {1, 2}\par\pard\li360\ri0\sl-333\slmult0 \fs16\cf0\f0\char
scalex100 {1}\fs22\cf0\f0\charscalex100 {Center for Molecular Imaging, Departmen
t of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA}\par\p
ard\li360\ri0\sl-333\slmult0 \fs24\cf0\f0\charscalex100 {and}{ }\fs16\cf0\f0\cha
rscalex100 {2}\fs22\cf0\f0\charscalex100 {Department of Microbiology and Immunol
ogy, University of Michigan Medical School, Ann Arbor, MI, USA}\par\pard\li360\r
i0\sl-266\slmult0 \fs12\cf0\f0\charscalex100 {BioTechniques}\fs12\cf0\f0\charsca
lex100 { 47:625-632 (July 2009) doi 10.2144/000113126 }\par\pard\li360\ri0\sl-22
6\slmult0 \fs12\cf0\f0\charscalex100 {Keywords: chemokine; bioluminescence; chem
okine receptor;}{ }\fs16\cf0\f0\charscalex100 {Gaussia}\fs16\cf0\f0\charscalex10
0 { luciferase}\par\pard\li360\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li360\ri0\s
l-320\slmult0 \fs24\cf0\f0\charscalex100 {Chemokine CXCL12 and its two known rec
eptors, CXCR4 and CXCR7, may play a role in diseases including}\par\pard\li360\r
i0\sl-306\slmult0 \fs20\cf0\f0\charscalex100 {tumor growth and metastasis, ather
osclerosis, and HIV infection. Therefore, these molecules may be promising tar}\
fs20\cf0\f0\charscalex100 {-}\par\pard\li360\ri0\sl-306\slmult0 \fs20\cf0\f0\cha
rscalex100 {gets for drug development. While studies of cell signaling and highthroughput screening for drug discovery increas}\fs20\cf0\f0\charscalex100 {-}\p
ar\pard\li360\ri0\sl-306\slmult0 \fs20\cf0\f0\charscalex100 {ingly are based on
luminescent assays because of their high sensitivity and signal-to-background ra
tio, there currently}\par\pard\li360\ri0\sl-306\slmult0 \fs22\cf0\f0\charscalex1
00 {is no bioluminescent assay for chemokine\uc1\u8211Xchemokine receptor bindin
g. To develop a bioluminescent probe for}\par\pard\li360\ri0\sl-333\slmult0 \fs2
0\cf0\f0\charscalex100 {chemokine binding and cellular uptake, we fused CXCL12 t
o}{ }\fs22\cf0\f0\charscalex100 {Gaussia}\fs20\cf0\f0\charscalex100 { luciferase
(GL), an ATP-independent enzyme}\par\pard\li360\ri0\sl-333\slmult0 \fs22\cf0\f0
\charscalex100 {that is the smallest known luciferase. Fusing CXCL12 to}{ }\fs24
\cf0\f0\charscalex100 {Gaussia}\fs22\cf0\f0\charscalex100 { luciferase (CXCL12-G
L) did not alter the biolu}\fs22\cf0\f0\charscalex100 {-}\par\pard\li360\ri0\sl306\slmult0 \fs20\cf0\f0\charscalex100 {minescence emission spectrum and only mi
nimally affected enzyme function under varying conditions of pH, tem}\fs20\cf0\f
0\charscalex100 {-}\par\pard\li360\ri0\sl-306\slmult0 \fs22\cf0\f0\charscalex100
{perature, and NaCl concentration. CXCL12-GL also activated CXCR4-dependent sig
naling to a comparable extent }\par\pard\li360\ri0\sl-306\slmult0 \fs22\cf0\f0\c
harscalex100 {as unfused CXCL12. Using multiwel plate assays, we established th
at CXCR7 increases cel -associated CXCL12}\par\pard\li360\ri0\sl-306\slmult0 \fs
22\cf0\f0\charscalex100 {to a significantly greater extent than CXCR4. We also s
howed that CXCL12-GL can be used to quantify inhibition}\par\pard\li360\ri0\sl-3
06\slmult0 \fs22\cf0\f0\charscalex100 {of chemokine receptor binding by compound
s that specifical y target CXCR7. These data validate CXCL12-GL as}\par\pard\li3
60\ri0\sl-306\slmult0 \fs22\cf0\f0\charscalex100 {a bioluminescent probe to inve
stigate molecular functions of CXCR4 and CXCR7 and screen for compounds that}\pa
r\pard\li360\ri0\sl-306\slmult0 \fs24\cf0\f0\charscalex100 {modulate ligand-rece
ptor binding.}\par\pard\sect\sectd\sbknone\cols3\colno1\colw3813\colsr-0\colno2\
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d\li360\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li360\ri0\sl-426\slmult0 \fs28\cf2

\f0\charscalex100 {Introduction}\par\pard\li360\ri0\sl-253\slmult0 \fs20\cf0\f0\
charscalex100 {Chemokines and chemokine receptors }\par\pard\li360\ri0\sl-253
\slmult0 \fs18\cf0\f0\charscalex100 {originally were identified as regulators of
}\par\pard\li360\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {immune cell tra
fficking in normal physi-}\par\pard\li360\ri0\sl-253\slmult0 \fs18\cf0\f0\charsc
alex100 {ology and inflammation. More recently, }\par\pard\li360\ri0\sl-253\slmu
lt0 \fs18\cf0\f0\charscalex100 {this family of proteins has been shown to }\par\
pard\li360\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {regulate diseases incl
uding cancer, athero}\fs18\cf0\f0\charscalex100 {-}\par\pard\li360\ri0\sl-253\sl
mult0 \fs18\cf0\f0\charscalex100 {sclerosis, autoimmune diseases, and neuro}\fs1
8\cf0\f0\charscalex100 {-}\par\pard\li360\ri0\sl-253\slmult0 \fs18\cf0\f0\charsc
alex100 {degenerative processes (1,2\uc1\u8211X4). As a result,}\par\pard\li360\
ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {chemokine receptors have emerged
as new}\par\pard\li360\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {therapeuti
c targets, emphasizing the need }\par\pard\li360\ri0\sl-253\slmult0 \fs18\cf0\f0
\charscalex100 {to develop reagents for quantitative, high-}\par\pard\li360\ri0\
sl-253\slmult0 \fs18\cf0\f0\charscalex100 {throughput screening assays of chemok
ine}\par\pard\li360\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {binding and i
nhibition.}\par\pard\li600\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {Conven
tional assays use radiolabeled }\par\pard\li360\ri0\sl-253\slmult0 \fs18\cf0\f0\
charscalex100 {chemokines to quantify binding to specific}\par\pard\li360\ri0\sl
-253\slmult0 \fs18\cf0\f0\charscalex100 {receptors and identify inhibitors of li
gand-}\par\pard\li360\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {receptor in
teractions. While radioligand }\par\pard\li360\ri0\sl-253\slmult0 \fs16\cf0\f0\c
harscalex100 {binding studies have been used successfully }\par\pard\li360\ri0\s
l-253\slmult0 \fs20\cf0\f0\charscalex100 {for these purposes, such assays genera
te}\par\pard\li360\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {radioactive wa
ste that is cumbersome to }\par\pard\li360\ri0\sl-253\slmult0 \fs18\cf0\f0\chars
calex100 {dispose. As alternatives to radioactivity, }\par\pard\li360\ri0\sl-253
\slmult0 \fs18\cf0\f0\charscalex100 {investigators increasingly are using fluore
s}\fs18\cf0\f0\charscalex100 {-}\par\pard\li360\ri0\sl-253\slmult0 \fs20\cf0\f0\
charscalex100 {cence or bioluminescence for cell-based}\par\pard\li360\ri0\sl-25
3\slmult0 \fs14\cf0\f0\charscalex100 {assays in basic research and high-throughp
ut }\par\pard\li360\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {screening. CX
CL12 and other chemokines }\par\pard\li360\ri0\sl-253\slmult0 \fs16\cf0\f0\chars
calex100 {have been labeled with fluorescent dyes or }\par\pard\li360\ri0\sl-253
\slmult0 \fs18\cf0\f0\charscalex100 {proteins to detect ligand-receptor binding
}\par\pard\li360\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {in intact cells
(5). For example, Hatse et al.}\par\pard\li360\ri0\sl-226\slmult0 \fs18\cf1\f0\c
harscalex100 {Vol. 47 | No. 1 | 2009}\par\column\pard\li0\ri0\sl-213\slmult0 \fs
18\cf0\par\pard\li0\ri0\sl-453\slmult0 \fs18\cf0\f0\charscalex100 {fused CXCL12
to AlexaFluor 647 and used }\par\pard\li0\ri0\sl-253\slmult0 \fs16\cf0\f0\charsc
alex100 {this reagent to detect binding and inhibition }\par\pard\li0\ri0\sl-253
\slmult0 \fs20\cf0\f0\charscalex100 {of CXCL12-CXCR4 interactions by }\par\pard\
li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {flow cytometry (6). Similarly
, binding of }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {CXCL1
2 to receptor CXCR7 has been }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\char
scalex100 {analyzed with a genetic fusion of CXCL12}\par\pard\li0\ri0\sl-253\slm
ult0 \fs18\cf0\f0\charscalex100 {to green fluorescent protein (GFP) (7).}\par\pa
rd\li240\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {Whilethesestudiesshowtha
tfluorescent }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {chemo
kines provide a viable replacement for }\par\pard\li0\ri0\sl-253\slmult0 \fs20\c
f0\f0\charscalex100 {radiolabeled chemokine binding assays in }\par\pard\li0\ri0
\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {some experimental settings, biolumin
es}\fs20\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\c
harscalex100 {cence assays have not been developed for }\par\pard\li0\ri0\sl-253
\slmult0 \fs20\cf0\f0\charscalex100 {chemokine-chemokine receptor binding }\par\
pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {studies. Relative to flu
orescence-based }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {te
chniques, bioluminescence assays with }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf

0\f0\charscalex100 {luciferase enzymes offer several potential }\par\pard\li0\ri
0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {advantages for quantifying accumula
tion}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {of chemokines
in intact cells (8). First, }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\chars
calex100 {bioluminescence assays have substantially }\par\pard\li0\ri0\sl-253\sl
mult0 \fs20\cf0\f0\charscalex100 {lower background signal than fluores}\fs20
\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscale
x100 {cence, enhancing signal-to-noise ratios for }\par\pard\li0\ri0\sl-253\slmu
lt0 \fs20\cf0\f0\charscalex100 {chemokine binding. Improved sensitivity }\par\pa
rd\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {is particularly important
for measuring }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {liga
nd binding to chemokine and other }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0
\charscalex100 {seven-transmembrane receptors because}\par\pard\li0\ri0\sl-253\s
lmult0 \fs18\cf0\f0\charscalex100 {these proteins may be expressed at modest}\pa
r\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {levels in cells (9). S
econd, bioluminescent }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex1
00 {end points have a greater dynamic range of}\par\pard\li0\ri0\sl-253\slmult0
\fs20\cf0\f0\charscalex100 {linear signal response than corresponding }\par\pard
\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {fluorescent probes. Finally,
bioluminescence }\par\pard\li1093\ri0\sl-453\slmult0 \fs36\cf1\f0\charscalex100
{625}\par\column\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-453\
slmult0 \fs18\cf0\f0\charscalex100 {assays are affected less than fluorescence}\
par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {by colors and dyes i
n compounds and cell }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex10
0 {culture media. These advantages account}\par\pard\li0\ri0\sl-253\slmult0 \fs2
0\cf0\f0\charscalex100 {for improved performance of biolumines}\fs20\cf0\f0\char
scalex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {cence
relative to fluorescence in multiwell }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf
0\f0\charscalex100 {cell culture formats and highlight the need }\par\pard\li0\r
i0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {for a bioluminescent assay of chem
okine-}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {chemokine re
ceptor binding (10).}\par\pard\li240\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex1
00 {To develop a bioluminescent assay for }\par\pard\li0\ri0\sl-253\slmult0 \fs2
0\cf0\f0\charscalex100 {binding of chemokines to receptors, we}\par\pard\li0\ri0
\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {focused on chemokine CXCL12 and its
two }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {known receptor
s, CXCR4 and CXCR7. }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100
{There is particular interest in developing }\par\pard\li0\ri0\sl-253\slmult0 \
fs20\cf0\f0\charscalex100 {specific inhibitors of CXCL12 binding }\par\pard\li0\
ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {to these two receptors both as ch
emical}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {probes for i
nvestigating specific mecha}\fs20\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-2
53\slmult0 \fs18\cf0\f0\charscalex100 {nisms of action and as potential therapeu
tic }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {agents for tre
ating diseases including cancer }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\c
harscalex100 {and HIV (11\uc1\u8211X13). We fused CXCL12 to }\par\pard\li0\ri0\s
l-253\slmult0 \fs20\cf0\f0\charscalex100 {the humanized form of luciferase from
}\par\pard\li0\ri0\sl-280\slmult0 \fs18\cf0\f0\charscalex100 {Gaussia princeps}\
fs20\cf0\f0\charscalex100 {.}{ }\fs20\cf0\f0\charscalex100 {Gaussia}\fs18\cf0\f0
\charscalex100 { luciferase (GL) is}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f
0\charscalex100 {the smallest known luciferase, containing }\par\pard\li0\ri0\sl
-253\slmult0 \fs18\cf0\f0\charscalex100 {only 185 amino acids. In cell-based ass
ays, }\par\pard\li0\ri0\sl-266\slmult0 \fs20\cf0\f0\charscalex100 {GL is}{ }\fs2
0\cf0\f0\charscalex100 {\uc1\u8764X}\fs20\cf0\f0\charscalex100 {1000 brighter tha
n firefly and }\par\pard\li0\ri0\sl-280\slmult0 \fs20\cf0\f0\charscalex100 {Reni
l a}\fs18\cf0\f0\charscalex100 { luciferases (two other enzymes used }\par\pard\
li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {commonly for bioluminescent a
ssays), which }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {incr
eases the dynamic range for detection }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf
0\f0\charscalex100 {and quantification (14). Bioluminescence }\par\pard\li0\ri0\

sl-253\slmult0 \fs20\cf0\f0\charscalex100 {from GL is also independent of ATP, }
\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {allowing the enzyme
to function in both }\par\pard\li1453\ri0\sl-226\slmult0 \fs16\cf1\f0\charscale
x100 {www.BioTechniques.com}\par\pard\sect\sectd\sbknone\pard\sect\sectd\sbkpage
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E1268709146578418072D9EA7F2F7F1AF0EFC3BB9B9F85CBE37D22F2E06B76570D3C48A7858E2272
147F7B2377E18AF7EF87DE32B7F1BF856DF538C85B94FDD5DC43F825039E3D0F51EC6803CDBC29E2
6F8A9E2DBCD520B2D4B448CE9971F679FCE808DC7247CB8078F94FA57B926ED8BBF1BB1CE3D6BC7F
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3AAD8ADC5BBC6464115E31E23F075C4372F2C09904E718AF7E92107A83EF59B73A6C53860C80FE14
01F35C9A45EC47981BF2A81AD2E13EF44DF957D073F872DE427F763F2AA327852DD8E0C43F2A00F0
EB7D3EE2790011B75EB8A2EED25B7976B211F5AF714F0BC10F2B128CFA0ACFD47C230DC8398D6803
C5726938C127AD7A749E0442D811F4A84F80573F74D0079D2A17701464D493C6F1BE1C1E9DEBD36C
FC13142C1BCBC91DCD2EA3E0D4B85FB983EC2803CAF81D697191915DBBF81640FC6714D1E05973D4
D0071316EF3576839CF6A9EF1A4DE0393D3BD7A0E99E051149BA4193536A9E095B85CA210DEB401E
5F4020678CD76C7C052E782697FE1029BA64E7E9401C523B2B0DA4835D03DE5D2E9230CC38EB5B96
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FA569D9A2E87DAB39BC01763D6803260F15EA11B0FDE13F8D7A27863C4735F5933383951D6B9387E
1F5E330CF4FA57A27873C2A34EB2F2C8C9239A00E275CF18DE437AF127183D6B2E3F1ADF0604935D
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8F973CD7276FF0E504EAC4719AEDED74316F61E428E318A00EE34897CFD1ECE5FEFC2ADFA55DAA5A
4C5E4691670FF72155FD2AED00145145001451450014514500145145001451450014514500145145
001451450014514500145145001451450014514500145145001451450047302D0B003248AA1F6772
7946FCAB4E8A00C9FB3BFF00CF26FCA90DAC841CC6DC7B56BD140195F6772388D80FA5345B49FC51
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10FE07FD28FED28B00EC7A00ABF6690702361F8506D9C8C18DFF002AB5FDA717F71FF2A3FB4A2FEE
3FE940153ECCE7FE59B7E2B47D95F77FAB6FCAADFF006945FDC7FD28FED28BFB8FFA50055FB2BF38
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7E9487518863E46E7E9401008A43D636FCA848643C94603D3153FF006945FDD6A5FED08F38DAD401
1794F9FB87F2A6BC5231C0561F854E2FE3271B5FF2A3EDF1FF0075A8021F29F23F76DF5C53842C4E
4AB1FA8A97EDD1F756A4FB7C7FDD6A006C51B0957E52003D48ABB557EDD1FF0075AA78E412C61C02
01F5A007D145140054177676D7F6B25ADE5BC5716F20C3C52A06561D79078353D14010DB5B41676D
1DB5AC31C3044BB5238D42AA8F40074ACFFF00845F40FED2FED1FEC5D3FEDBBB77DA3ECC9BF3EB9C
673EF5AD450051D4F46D335A8922D534FB5BD8E36DC8B7112B853EA3238A82E7C35A15E5C417173A
369F34D6EA161792D918C60740091C01DBD2B568A00CA6F0CE84F6B2DAB68D606DE597CE92236C9B
1E4FEF118C13EF5A0F6F0CB6CD6D2428D032796D195054AE318C7A638C54B450055B0D3AC74AB6FB
369F6705A40096F2E08C22E4F538150CBA16933DE4B7936996725CCD198A599A052EE8460A938C91
8E315A1450056B2D3ECB4DB45B4B1B482DAD8671143184519EBC0E2A1D3F45D2F48329D374EB4B33
29064FB3C2B1EFC74CE073D6AFD14014ECB4AD3F4D79DEC6C6DAD9A76DF3186208646E796C753C9F
CEAE51450014514500155AFA3692DF6A824E4702ACD1401826D671D217FCA90D8CC7FE593FE55BF4
500738DA74C47FA86CFD29874DB8E9E4B63E95D351401CB3697719FF0050E47A629ADA4CE47FA86F
6E2BABA28038F3A3CEC39B67CFD29A746B8FF9F67FC05765450071BFD8D718FF008F77FCA91B45B8
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F4A71D16720E6D9BF2AEC28A00E33FB065FF009F67FCA9468537FCFB37E55D951401C8AE8B2AE716
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003EE73F4A946992818F21B18F4AE928A00E59B48949C981BF2A43A24871980FE55D551401CCAE90
EA46203F954F1E9CEB81E4B015BF4500611B1946311311F4A51A7BE0E623F956E514018696122807
CA6CF7E29DF6294AF11B0E2B6A8A008EDD4A5BC6A4608500D4945140051451400514514005145140
051451400514514005145140051451400514514005145719F113C747C17A6DA0B4B237DAAEA13791
676DD99B8C938E7B8E3B922803B3A2BC8EE7C61F133C2D756571E23D02C2FB4EBA9446EBA52BBCD0
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004AE4E5D5E14E19C71EF401D009063AE7DE94480B5738BADC24E3CD18EFCD5A8F52493F8C67B60D
006C79A79FD680FCFB7A5670B91EA3EB9A89B5145CE587D280363CC03FFD74AB21EB8AC41A8C4318
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1906B62D3FE3D53FCF7A009E8A28A0028A28A0028A28A0028A28A0028A28A0028A28A0028A28A002
8A28A0028A28A0028A28A0028A28A0028A28A0028A28A0028A28A002BC8BE32B49A4F883C17E2796
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278AF54D33E1E68F0C52EA5712ACF72F22E7ECC00C8E7B1C649F6C0EF5E93A57823C31A1DF0BDD33
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81F95007977C28D498787B58F8757F0A58EB3A7ACD1A8E9E72BE7E61EA413D7B820D43F077C5FA27
86FC2777E1FD7AFA2D2F51D3AE6532C774DE5965273919EA7A8C75E9EB5EAF2786B45975D4D71F4C
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23023C039C6D1C75E6B17FE1597823FE858D37FEFC8A00C7F8BB0DA1F859E20BD82287CCB88612D3
228DD2289136E5BB8C74A966F17D97823E12691ABDE0F31869F6E90400E0CB218C617FA93D8035D8
DEE93A7EA3A5B699796914F62CAA86075CA10082063DB03F2AA9A8F85741D5AC2D6C2FF4AB5B9B4B
400410C89958C018181F4E2803C9BE19DE693AF78BD7C51E22F10595DF89EF54A5969F137FC7AA60
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AA7F9EF4013D14514005145140051451400514514005145140051451400514514005145140051451
40051451400514514005145140051451400514514005145140051451400514514005145140051451
40051451400514514005145140051451400514514005145140051451400514514005145140051451
40051451400514514005145140051451400514514005145140051451400514514005145140051451
4005145140051451400514514014B51824B88D046BB886C9E6B37FB2A72C58C63E9915BF450073DF
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2BA4A28039B5D125041F287D322A45D22503FD50CFD457414500618D3675390807E2295B4D9881FB
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28A00C9FB14F8FB9FAD385A4C07DCFD6B528A00CB36929E7674E9CD5FB7468E0556E1854B4500145
14500145145001451450014514500145145001451450014514500145145001451450014514500145
14500145145001451450014514500145145001451450014514500145145001451450014514500145
14500145145001451450014514500145145001451450014514500145145001451450014514500145
14500145145001451450014514500145145001451450014514500145145001451450014514500145
14500145145001451450014514500145145001451450014514500145145001451450014514500145
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14500145145001451450014514500145145001451450014514500145145001451450014514500145
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1450014514500145145001451450014514500145145007FFD9}
}}}}\pgwsxn11880\pghsxn15560\marglsxn666\margrsxn133\margtsxn573\margbsxn66\cols
3\colno1\colw3680\colsr-0\colno2\colw3480\colsr-0\colno3\colw3920\pard\li133\ri0
\sl-186\slmult0 \fs16\cf1\f0\charscalex100 {Research Reports}\par\pard\li120\ri0
\sl-213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl-440\slmult0 \fs20\cf0\f0\charsca
lex100 {intracellular and extracellular compart}\fs20\cf0\f0\charscalex100 {-}\p
ar\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {ments (15). While o
ur studies focus on }\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex1
00 {CXCL12, we expect this technique can }\par\pard\li120\ri0\sl-253\slmult0 \fs
16\cf0\f0\charscalex100 {be generalized to develop bioluminescent }\par\pard\li1
20\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {probes for other chemokines an
d other }\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {peptide
signaling molecules.}\par\pard\li120\ri0\sl-373\slmult0 \fs28\cf2\f0\charscalex1
00 {Materials and methods}\par\pard\li120\ri0\sl-240\slmult0 \fs20\cf2\f0\charsc
alex100 {Cells}\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {29
3T cells (Open Biosystems, Huntsville,}\par\pard\li120\ri0\sl-253\slmult0 \fs16\
cf0\f0\charscalex100 {AL, USA), and human breast cancer cell }\par\pard\li120\ri
0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {lines MDA-MB-231 and MCF-7 (ATCC, }
\par\pard\li120\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {Manassas, VA, U
SA) were cultured at }\par\pard\li120\ri0\sl-253\slmult0 \fs16\cf0\f0\charsca
lex100 {37C and 5% CO}\fs10\cf0\f0\charscalex100 {2}\fs18\cf0\f0\charscalex100 {
in DMEM (Invitrogen, }\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex
100 {Carlsbad, CA, USA), 10% fetal bovine}\par\pard\li120\ri0\sl-253\slmult0 \fs
18\cf0\f0\charscalex100 {serum, 1% glutamine, and 0.1% penicillin/}\par\pard\li1
20\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {streptomycin/gentamicin (Invit
rogen).}\par\pard\li120\ri0\sl-240\slmult0 \fs20\cf2\f0\charscalex100 {DNA const
ructs}\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {Mouse CXCL1
2-\uc1\u945X was amplified by PCR}\par\pard\li120\ri0\sl-253\slmult0 \fs16\cf0\f
0\charscalex100 {usingplasmidCXCL12-degrakine (courtesy }\par\pard\li120\ri0\sl253\slmult0 \fs16\cf0\f0\charscalex100 {of Lishan Su, University of North Caroli
na, }\par\pard\li120\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {Chapel Hill,
NC, USA) as a template. PCR }\par\pard\li120\ri0\sl-266\slmult0 \fs18\cf0\f0\ch
arscalex100 {primers were 5}\fs20\cf0\f0\charscalex100 {\uc1\u8242X}\fs20\cf0\f0
\charscalex100 {- ATGC}\fs20\cf0\f0\charscalex100 {CTCGAG}\fs20\cf0\f0\charscale
x100 {GCCA}\fs20\cf0\f0\charscalex100 {-}\par\column\pard\li0\ri0\sl-213\slmult0
\fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-466\slm
ult0 \fs24\cf0\f0\charscalex100\b {A}\b0 \par\pard\li0\ri0\sl-213\slmult0 \fs18\
cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \f
s18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult
0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\sl
mult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-21
3\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\s
l-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\r
i0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-373\slmult0 \fs24\cf0\f0\charsca
lex100\b {C}\b0 \par\column\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\r
i0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-466\slmult0 \fs24\cf0\f0\charsca
lex100\b {B}\b0 \par\pard\sect\sectd\sbknone\pgwsxn11880\pghsxn15560\marglsxn666
\margrsxn133\cols2\colno1\colw3600\colsr-0\colno2\colw7480\pard\li120\ri0\sl-280
\slmult0 \fs20\cf0\f0\charscalex100 {CCATGGACGCCAAGGTCGTCG-3}\fs20\cf0\f0\charsc
alex100 {\uc1\u8242X}\par\pard\li120\ri0\sl-280\slmult0 \fs18\cf0\f0\charscalex1
00 {and 5}\fs18\cf0\f0\charscalex100 {\uc1\u8242X}\fs18\cf0\f0\charscalex100 {-G
CATGAATTC}\fs18\cf0\f0\charscalex100 {CCCTTGTT}\fs18\cf0\f0\charscalex100 {-}\pa
r\pard\li120\ri0\sl-266\slmult0 \fs18\cf0\f0\charscalex100 {TA A AGCTTTCTCCAGGTA
-3}\fs18\cf0\f0\charscalex100 {\uc1\u8242X}\fs18\cf0\f0\charscalex100 {;}\par\pa
rd\li120\ri0\sl-280\slmult0 \fs16\cf0\f0\charscalex100 {restriction sites for}\f
s18\cf0\f0\charscalex100 {Xho}\fs18\cf0\f0\charscalex100 {I and}{ }\fs18\cf0\f0\
charscalex100 {Eco}\fs16\cf0\f0\charscalex100 {RI, respec}\fs16\cf0\f0\charscale
x100 {-}\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {tively, a
re underlined. The PCR product}\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\c

harscalex100 {was ligated to the corresponding sites in}\par\pard\li120\ri0\sl-2
53\slmult0 \fs18\cf0\f0\charscalex100 {plasmid EGFP-N1 (BD Biosciences, San }\pa
r\pard\li120\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {Jose, CA, USA). GL w
as amplified using }\par\pard\li120\ri0\sl-280\slmult0 \fs20\cf0\f0\charscalex10
0 {PCR primers 5}\fs20\cf0\f0\charscalex100 {\uc1\u8242X}\fs20\cf0\f0\charscalex
100 {-ATGCGAATTC}\fs20\cf0\f0\charscalex100 {CG}\fs20\cf0\f0\charscalex100 {-}\p
ar\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {GCGGAGGTGGGTCCGGAGG
CG}\fs20\cf0\f0\charscalex100 {-}\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f0
\charscalex100 {GTGGGAGCGCCA AGCCCAC}\fs20\cf0\f0\charscalex100 {-}\par\pard\li1
20\ri0\sl-266\slmult0 \fs20\cf0\f0\charscalex100 {CGAGAACAACGAAGACTTC-3}\fs20\cf
0\f0\charscalex100 {\uc1\u8242X}\par\pard\li120\ri0\sl-280\slmult0 \fs20\cf0\f0\
charscalex100 {and 5}\fs20\cf0\f0\charscalex100 {\uc1\u8242X}\fs20\cf0\f0\charsc
alex100 {- GCAT}\fs20\cf0\f0\charscalex100 {GCGGCCGC}\fs20\cf0\f0\charscalex100
{TTAGC}\fs20\cf0\f0\charscalex100 {-}\par\pard\li120\ri0\sl-280\slmult0 \fs18\cf
0\f0\charscalex100 {CTATGCCGCCCTGTGCGG-3}\fs18\cf0\f0\charscalex100 {\uc1\u8242X
}\fs18\cf0\f0\charscalex100 { with }\par\pard\li120\ri0\sl-280\slmult0 \fs20\cf0
\f0\charscalex100 {Eco}\fs20\cf0\f0\charscalex100 {RI and }\fs20\cf0\f0\charscal
ex100 {Not}\fs20\cf0\f0\charscalex100 {I restriction sites under}\fs20\cf0\f0\ch
arscalex100 {-}\par\pard\li120\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {li
ned (pGLuc-Basic, New England Biolabs, }\par\pard\li120\ri0\sl-253\slmult0 \fs16
\cf0\f0\charscalex100 {Ipswich, MA, USA). This strategy removes }\par\pard\li120
\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {the 15\uc1\u8211Xamino acid secr
etion signal from }\par\pard\li120\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100
{GL and inserts a (G}\fs10\cf0\f0\charscalex100 {4}\fs18\cf0\f0\charscalex100 {
S)}\fs10\cf0\f0\charscalex100 {2}\fs18\cf0\f0\charscalex100 { amino acid linker
}\par\pard\li120\ri0\sl-280\slmult0 \fs18\cf0\f0\charscalex100 {between CXCL12 a
nd}{ }\fs20\cf0\f0\charscalex100 {Gaus ia}\fs18\cf0\f0\charscalex100 { (designat
ed }\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {as CXCL12-GL)
. CXCL12-GL and the }\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex1
00 {cytomegalovirus (CMV) promoter from }\par\pard\li120\ri0\sl-253\slmult0 \fs1
6\cf0\f0\charscalex100 {EGFP-N1 were removed with restriction }\par\pard\li120\r
i0\sl-280\slmult0 \fs18\cf0\f0\charscalex100 {enzymes }\fs16\cf0\f0\charscalex10
0 {Ase}\fs18\cf0\f0\charscalex100 {I and}{ }\fs18\cf0\f0\charscalex100 {Not}\fs1
8\cf0\f0\charscalex100 {I and ligated to the }\par\pard\li120\ri0\sl-280\slmult0
\fs18\cf0\f0\charscalex100 {blunted }\fs18\cf0\f0\charscalex100 {Pac}\fs16\cf0\
f0\charscalex100 {I site of FUPW (16). Unfused }\par\pard\li120\ri0\sl-253\slmul
t0 \fs18\cf0\f0\charscalex100 {CXCL12 was inserted into the blunted }\par\pard\l
i120\ri0\sl-280\slmult0 \fs20\cf0\f0\charscalex100 {Eco}\fs18\cf0\f0\charscalex1
00 {RI site of EGFP-N1 and then transferred }\par\pard\li120\ri0\sl-253\slmult0
\fs18\cf0\f0\charscalex100 {to FUPW as described for CXCL12-GL.}\par\pard\li120\
ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {GL was excised from pGLuc-Basic w
ith }\par\pard\li120\ri0\sl-280\slmult0 \fs18\cf0\f0\charscalex100 {Eco}\fs18\cf
0\f0\charscalex100 {RI and}{ }\fs18\cf0\f0\charscalex100 {Not}\fs16\cf0\f0\chars
calex100 {I and inserted into FUPW as }\par\pard\li120\ri0\sl-253\slmult0 \fs16\
cf0\f0\charscalex100 {described for CXCL12-GL. PCR products }\par\pard\li120\ri0
\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {were verified by DNA sequencing.}\pa
r\pard\li360\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {Human CXCR7 regulate
d by a human }\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {EF1\uc1\u945X promoter was inserted into the}\par\pard\li120\ri0\sl-280\slmul
t0 \fs20\cf0\f0\charscalex100 {blunted }\fs20\cf0\f0\charscalex100 {Eco}\fs18\cf
0\f0\charscalex100 {RI site of lentiviral vector }\par\pard\li120\ri0\sl-253
\slmult0 \fs18\cf0\f0\charscalex100 {pSico (courtesy of Tyler Jacks, Massachu}\
fs18\cf0\f0\charscalex100 {-}\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\cha
rscalex100 {setts Institute of Technology, Cambridge,}\par\pard\li120\ri0\sl-253
\slmult0 \fs16\cf0\f0\charscalex100 {MA, USA) (17,18). Human CXCR4 fused }\par\p
ard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {to GFP (CXCR4-GFP) (Pet
er Hordijk, }\par\column\pard\li0\ri0\sl-186\slmult0 \fs12\cf0\f0\charscalex100\
b {Figure 1. Secreted CXCL12-GL activates CXCR4 signaling.}\b0 \fs16\cf0\f0\char
scalex100 { (A) Cell culture supernatants were collected }\par\pard\li0\ri0\sl-1
86\slmult0 \fs16\cf0\f0\charscalex100 {from 293T cells stably transduced with CX

CL12-GL. Levels of CXCL12 were quantified by ELISA, }\par\pard\li0\ri0\sl-186\sl
mult0 \fs16\cf0\f0\charscalex100 {and bioluminescence from CXCL12-GL was measure
d using an IVIS imaging system (Caliper). Data }\par\pard\li0\ri0\sl-186\slmult0
\fs16\cf0\f0\charscalex100 {are shown for 3 independent preparations of CXCL12GL. (B) Human MDA-MB-231 breast cancer }\par\pard\li0\ri0\sl-186\slmult0 \fs16\c
f0\f0\charscalex100 {cells were stably transduced with lentiviruses for CXCR4-GF
P (231-CXCR4), CXCR7 (231-CXCR7), }\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0
\charscalex100 {or GFP control (231-control). Expression of CXCR4 or CXCR7 on th
e cell membrane was determined }\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\ch
arscalex100 {by flow cytometry. The open plot on the histogram denotes staining
with isotype control antibody }\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\cha
rscalex100 {when distinguishable from staining with the relevant MAb (filled plo
t). (C) 231-CXCR4 cells were }\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\char
scalex100 {starved of serum overnight and then incubated for 10 min with serial
dilutions of supernatants from }\par\pard\li0\ri0\sl-186\slmult0 \fs14\cf0\f0\ch
arscalex100 {293T cells stably expressing either CXCL12-GL or CXCL12. Amounts of
CXCL12-GL and CXCL12 in }\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\charscal
ex100 {undiluted supernatants were 30 ng/mL and 22 ng/mL, respectively. Parallel
cultures of 231-CXCR4 }\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\charscalex
100 {cells were incubated with synthetic CXCL12 diluted in conditioned medium fr
om untransduced }\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\charscalex100 {29
3T cells to match conditions for CXCL12-GL and CXCL12. Cells were lysed and anal
yzed by }\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\charscalex100 {Western bl
otting for levels of activated AKT, as determined by phosphorylation at serine 4
73 (P-473 }\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\charscalex100 {AKT). Bl
ots were stripped and re-probed for amounts of total AKT as a loading control.}\
par\pard\li0\ri0\sl-333\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {Landsteiner
Laboratorium, Amsterdam,}\tab \fs20\cf0\f0\charscalex100 {(BD Biosciences) to C
XCR4 and 11G8}\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\charscalex1
00 {The Netherlands) and a human EF-1\uc1\u945X }\tab \fs18\cf0\f0\charscalex100
{MAb (gift of ChemoCentryx, Mountain }\par\pard\li0\ri0\sl-253\slmult0 \*\tx348
0\fs20\cf0\f0\charscalex100 {promoter were inserted into pSico at }\tab \fs
20\cf0\f0\charscalex100 {View, CA, USA) to CXCR7 (22). 11G8}\par\pard\li0\ri0\sl
-280\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {blunted}{ }\fs20\cf0\f0\charsc
alex100 {Eco}\fs20\cf0\f0\charscalex100 {RI and}{ }\fs20\cf0\f0\charscalex100 {N
ot}\fs20\cf0\f0\charscalex100 {I sites, removing }\tab \fs16\cf0\f0\charscalex10
0 {binding was revealed with a goat anti-rabbit }\par\pard\li0\ri0\sl-253\slmult
0 \*\tx3480\fs18\cf0\f0\charscalex100 {unfused GFP from the vector (19).}\tab \f
s16\cf0\f0\charscalex100 {secondary antibody conjugated to DyLight }\par\pard\li
3480\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {488 (493-nm excitation/518-n
m emission) }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf2\f0\charscalex10
0 {Lentiviruses and transduction}\tab \fs16\cf0\f0\charscalex100 {(Jackson Immun
oResearch, West Grove, }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\c
harscalex100 {Replication-incompetent lentiviruses }\tab \fs18\cf0\f0\charscale
x100 {PA, USA).}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {wer
e prepared as described previously }\par\pard\li0\ri0\sl-253\slmult0 \*\tx34
80\fs20\cf0\f0\charscalex100 {(20,21) and used to stably transduce}\tab \fs
20\cf2\f0\charscalex100 {CXCL12-GL and GL supernatants}\par\pard\li0\ri0\sl-253\
slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {293T cells with CXCL12-GL, unfused
}\tab \fs18\cf0\f0\charscalex100 {Confluent 293T cells were cultured }\par\p
ard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {CXCL12, or GL. L
entiviruses based on }\tab \fs18\cf0\f0\charscalex100 {overnight in DMEM contain
ing 0.2% }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {
pSico viruses were used to stably transduce }\tab \fs16\cf0\f0\charscalex100 {BS
A (Probumin, Celliance, Norcross, GA, }\par\pard\li0\ri0\sl-253\slmult0 \*\tx348
0\fs18\cf0\f0\charscalex100 {human MDA-MB-231 breast cancer cells}\tab \fs16\cf0
\f0\charscalex100 {USA). Supernatants were centrifuged at }\par\pard\li0\ri0\sl280\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {with CXCR4-GFP, CXCR7, or GFP }
\tab \fs18\cf0\f0\charscalex100 {4000 }\fs18\cf0\f0\charscalex100 {g}{ }\fs16\cf0
\f0\charscalex100 {for 10 min (OmniSpin R; Sorvall, }\par\pard\li0\ri0\sl-253\sl

mult0 \*\tx3480\fs18\cf0\f0\charscalex100 {control. Resulting cells were designa
ted as }\tab \fs16\cf0\f0\charscalex100 {Thermo Fisher Scientific, Sugar Land, T
X, }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {231-CX
CR4, 231-CXCR7, or 231-control, }\tab \fs18\cf0\f0\charscalex100 {USA) to remove
cell debris prior to use in}\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf0
\f0\charscalex100 {respectively.}\tab \fs20\cf0\f0\charscalex100 {experiments.}\
par\pard\li0\ri0\sl-240\slmult0 \*\tx3480\fs20\cf2\f0\charscalex100 {Flow cytome
try}\tab \fs20\cf2\f0\charscalex100 {Emission spectrum}\par\pard\li0\ri0\sl-253\
slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {Cell surface expression of CXCR4 an
d }\tab \fs16\cf0\f0\charscalex100 {Bioluminescence spectra from CXCL12-GL }\par
\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {CXCR7 was dete
rmined as described }\tab \fs18\cf0\f0\charscalex100 {and GL were measured by di
luting super}\fs18\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \*\t
x3480\fs18\cf0\f0\charscalex100 {previously (22) using monoclonal antibody }\tab
\fs20\cf0\f0\charscalex100 {natants from 293T cells 1:100 in PBS at}\par\pard\l
i0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {12G5 directly conjuga
ted to phycoerythrin }\tab \fs18\cf0\f0\charscalex100 {a final volume of 200 \uc
1\u956XL. After adding }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\c
harscalex100 {(PE) (480-nm excitation/578-nm emission) }\tab \fs18\cf0\f0\charsc
alex100 {20 \uc1\u956Xg coelenterazine substrate for GL }\par\pard\sect\sectd\sb
knone\pgwsxn11880\pghsxn15560\marglsxn666\margrsxn133\cols3\colno1\colw4880\cols
r-0\colno2\colw3613\colsr-0\colno3\colw2586\pard\li120\ri0\sl-213\slmult0 \fs18\
cf0\par\pard\li120\ri0\sl-360\slmult0 \fs18\cf1\f0\charscalex100 {Vol. 47 | No.
1 | 2009}\par\column\pard\li0\ri0\sl-640\slmult0 \fs36\cf1\f0\charscalex100 {626
}\par\column\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-360\slmul
t0 \fs16\cf1\f0\charscalex100 {www.BioTechniques.com}\par\pard\sect\sectd\sbknon
e\pgwsxn11880\pghsxn15560\marglsxn666\margrsxn133\pard\sect\sectd\sbkpage
7;32768}}
7;32768}}

7;32768}}
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5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;24577;32768}}
,40);(13,40);(13,26);(13,26);(13,26);(13,26);(13,26);(13,26);(13,26);(13,26);(13
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5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;4
5824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;1;45824;245
77;32768}}
{\shp{\*\shpinst\shpleft-226\shptop7986\shpright12160\shpbottom7986\shpfhdr0\shp
{\sp{\sn fLayoutInCell}{\sv 1}}}}\pgwsxn11880\pghsxn15560\marglsxn186\margrsxn13
\margtsxn573\margbsxn0\cols3\colno1\colw4320\colsr-0\colno2\colw3480\colsr-0\col
no3\colw3880\pard\li840\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li840\ri0\sl-213\s
lmult0 \fs18\cf0\par\pard\li840\ri0\sl-413\slmult0 \fs20\cf0\f0\charscalex100 {(
Cat. no. 07372, Fluka, St. Louis, MO, }\par\pard\li840\ri0\sl-253\slmult0 \fs18\
cf0\f0\charscalex100 {USA), light emission at room temperature}\par\pard\li840\r
i0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {was recorded with a PerkinElmer LS
50B }\par\pard\li840\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {fluorimeter
(model no. S2001; Waltham, }\par\pard\li840\ri0\sl-253\slmult0 \fs18\cf0\f0\char
scalex100 {MA, USA) using scanning intervals of 0.5}\par\pard\li840\ri0\sl-253\s
lmult0 \fs18\cf0\f0\charscalex100 {nm. Relative to cell culture experiments, }\p
ar\pard\li840\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {a higher concentrat
ion of coelenterazine}\par\pard\li840\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex

100 {was used to increase the strength of biolu}\fs18\cf0\f0\charscalex100 {-}\p
ar\pard\li840\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {minescence signal a
nd prevent depletion of }\par\pard\li840\ri0\sl-253\slmult0 \fs18\cf0\f0\charsca
lex100 {substrate during the period of collection.}\par\pard\li840\ri0\sl-240\sl
mult0 \fs20\cf2\f0\charscalex100 {ELISA}\par\pard\li840\ri0\sl-253\slmult0 \fs16
\cf0\f0\charscalex100 {CXCL12 levels in supernatants from 293T }\par\pard\li840\
ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {cells stably transduced with CXCL
12-GL }\par\pard\li840\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {or CXCL12
were quantified by ELISA }\par\pard\li840\ri0\sl-253\slmult0 \fs18\cf0\f0\charsc
alex100 {(Quantikine; R&D Systems, Minneapolis,}\par\pard\li840\ri0\sl-253\slmul
t0 \fs20\cf0\f0\charscalex100 {MN, USA).}\par\pard\li840\ri0\sl-240\slmult0 \fs2
0\cf2\f0\charscalex100 {CXCL12-GL and GL stability}\par\pard\li840\ri0\sl-253\sl
mult0 \fs18\cf0\f0\charscalex100 {Effects of pH on bioluminescence from }\par\pa
rd\li840\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {CXCL12-GL and GL were me
asured in}\par\pard\li840\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {solutio
ns of PBS or 33-mM Tris-HCl with }\par\pard\li840\ri0\sl-253\slmult0 \fs16\cf0\f
0\charscalex100 {pH ranging 2.9\uc1\u8211X10.0. We combined 10 \uc1\u956XL }\par
\pard\li840\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {CXCL12-GL or GL super
natant with 190 }\par\pard\li840\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {
\uc1\u956XL buffer solution and incubated for 15 min }\par\pard\li840\ri0\sl-253
\slmult0 \fs18\cf0\f0\charscalex100 {at room temperature before measuring }\par\
pard\li840\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {bioluminescence. The s
ame procedure was }\par\pard\li840\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100
{used to test effects of various concentra}\fs18\cf0\f0\charscalex100 {-}\par\p
ard\li840\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {tions of NaCl solution
in water (0\uc1\u8211X1 M) }\par\pard\li840\ri0\sl-253\slmult0 \fs20\cf0\f0\char
scalex100 {on CXCL12-GL and GL. To measure}\par\pard\li840\ri0\sl-253\slmult0 \f
s16\cf0\f0\charscalex100 {thermal stability of CXCL12-GL and GL, }\par\column\pa
rd\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\pa
r\pard\li0\ri0\sl-413\slmult0 \fs18\cf0\f0\charscalex100 {60 \uc1\u956XL each su
pernatant were incubated at}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charsc
alex100 {37\uc1\u8211X65C in a PCR machine for 60 min. }\par\pard\li0\ri0\sl-253\
slmult0 \fs18\cf0\f0\charscalex100 {Bioluminescence was measured immedi}\fs18\cf
0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex10
0 {ately after incubation, using 10 \uc1\u956XL }\par\pard\li0\ri0\sl-253\s
lmult0 \fs18\cf0\f0\charscalex100 {CXCL12-GL or GL combined with 190 \uc1\u956XL
}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {PBS, pH 7.4.}\par
\pard\li240\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {Bioluminescence was
quantified by }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {ad
ding coelenterazine (1 \uc1\u956Xg/\uc1\u956XL solution }\par\pard\li0\ri0\sl-25
3\slmult0 \fs20\cf0\f0\charscalex100 {in methanol) at a final concentration of }
\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {1 \uc1\u956Xg/mL to
solutions of CXCL12-GL }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscale
x100 {or GL aliquoted in black-walled 96-well }\par\pard\li0\ri0\sl-253\slmult0
\fs20\cf0\f0\charscalex100 {plates (Cat. no. 07-200-627; Costar, }\par\pard\
li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {Thermo Fisher Scientific). GL
activity was }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {meas
ured immediately after adding coelen}\fs18\cf0\f0\charscalex100 {-}\par\pard\li0
\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {terazine using an IVIS 100 syste
m (Caliper, }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {Hopkin
ton, MA, USA). Imaging was done }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\c
harscalex100 {with 5\uc1\u8211X20-s acquisition times and high-}\par\pard\li0\ri
0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {resolution binning. Data were quant
ified }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {by region of
interest analysis using Living }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\c
harscalex100 {Image 2.6 (Caliper).}\par\pard\li0\ri0\sl-240\slmult0 \fs20\cf2\f0
\charscalex100 {Live cell imaging}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\
charscalex100 {Cells were plated in black-walled 96-well }\par\pard\li0\ri0\sl-2
53\slmult0 \fs20\cf0\f0\charscalex100 {plates (1 10}\fs12\cf0\f0\charscalex100 {
4}\fs20\cf0\f0\charscalex100 { cells per well) using }\par\pard\li0\ri0\sl-2

53\slmult0 \fs20\cf0\f0\charscalex100 {a Multidrop 384 dispensing system }\pa
r\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {(Labsystems, Waltham,
MA, USA), and}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {exper
iments were performed the subse}\fs20\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\
sl-253\slmult0 \fs20\cf0\f0\charscalex100 {quent day. Cells were incubated with
}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {various dilutions
of CXCL12-GL or GL }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100
{supernatants as described in figure legends. }\par\pard\li0\ri0\sl-253\slmult0
\fs20\cf0\f0\charscalex100 {For competition experiments, cells were}\par\column\
pard\li1880\ri0\sl-186\slmult0 \fs16\cf1\f0\charscalex100 {Research Reports}\par
\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-440\slmult0 \fs18\cf0
\f0\charscalex100 {incubated with CXCL12 (R&D Systems); }\par\pard\li0\ri0\sl-25
3\slmult0 \fs20\cf0\f0\charscalex100 {CXCR4 antagonist AMD3100 (Sigma-}\par\pard
\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {Aldrich, St. Louis, MO, USA)
; or CXCR7 }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {antagon
istsCCX733orCCX754(courtesy }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\chars
calex100 {of ChemoCentryx) added 30 min before }\par\pard\li0\ri0\sl-253\slmult0
\fs18\cf0\f0\charscalex100 {incubating cells with CXCL12-GL for 2 h }\par\pard\
li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {at 37C. Cells then were washed
twice with }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {PBS be
fore measuring cell-associated biolu}\fs18\cf0\f0\charscalex100 {-}\par\pard\li0
\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {minescence. One milligram per mi
lliliter }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {coelenter
azine in PBS was added to intact}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\c
harscalex100 {cells, and bioluminescence was measured }\par\pard\li0\ri0\sl-253\
slmult0 \fs20\cf0\f0\charscalex100 {immediately after adding substrate as }\par\
pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {described above.}\par\pa
rd\li0\ri0\sl-240\slmult0 \fs20\cf2\f0\charscalex100 {Western blots}\par\pard\li
0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {231-CXCR4, 231-CXCR7, and 231-G
FP }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {control cells w
ere incubated overnight in }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charsc
alex100 {DMEM medium containing 0.2% BSA.}\par\pard\li0\ri0\sl-253\slmult0 \fs20
\cf0\f0\charscalex100 {Cells then were treated with superna}\fs20\cf0\f0\charsca
lex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {tants fro
m 293T cells stably expressing }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\ch
arscalex100 {CXCL12, CXCL12-GL, or GL for 10}\par\pard\li0\ri0\sl-253\slmult0 \f
s18\cf0\f0\charscalex100 {min. 231-CXCR4 cells also were treated }\par\pard\li0\
ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {for 10 min with various concentra
tions of}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {synthetic
CXCL12 (R&D Systems) added }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charsc
alex100 {to conditioned medium from 293T cells. }\par\pard\li0\ri0\sl-253\slmult
0 \fs18\cf0\f0\charscalex100 {Cellswerelysedasdescribedpreviously(16). }\par\par
d\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {Lysates were probed for AKT
phosphory}\fs18\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \fs18\
cf0\f0\charscalex100 {lated at serine 473 to assess activation of }\par\pard\li0
\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {CXCR4 signaling, using a 1:500 d
ilution}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {of primary
antibody (Cell Signaling, }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charsca
lex100 {Danvars, MA, USA). Primary antibodies}\par\pard\sect\sectd\sbknone\pgwsx
n11880\pghsxn15560\marglsxn186\margrsxn13\cols2\colno1\colw8253\colsr-0\colno2\c
olw3426\pard\li133\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li133\ri0\sl-213\slmult
0 \fs18\cf0\par\pard\li133\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li133\ri0\sl-60
0\slmult0 \fs46\cf3\f0\charscalex100 {Where Quality meets E ciency}\par\pard\li
4173\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li4173\ri0\sl-213\slmult0 \fs18\cf0\p
ar\pard\li4173\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li4173\ri0\sl-80\slmult0 \f
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0\par\pard\li226\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li226\ri0\sl-320\slmult0
\fs16\cf0\f0\charscalex100 {NuAire\uc1\u8217Xs}\fs8\cf0\f0\charscalex100 {}\fs16\
cf0\f0\charscalex100 { CellGard ES}\fs8\cf0\f0\charscalex100 {\uc1\u8482X}\fs16\
cf0\f0\charscalex100 { NU-480 Class II, Type A2 Biological Safety}\par\pard\li22

6\ri0\sl-280\slmult0 \fs16\cf0\f0\charscalex100 {Cabinet uses the best of our ex
isting technologies and the best of}\par\pard\li226\ri0\sl-280\slmult0 \fs16\cf0
\f0\charscalex100 {the new DC ECM motor technology to provide lower energy costs
,}\par\pard\li226\ri0\sl-280\slmult0 \fs16\cf0\f0\charscalex100 {longer \uc1\u64
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0 {}\fs16\cf0\f0\charscalex100 { uses}\par\pard\li226\ri0\sl-280\slmult0 \fs16\c
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r square inch; the}\par\pard\li226\ri0\sl-280\slmult0 \fs16\cf0\f0\charscalex100
{TouchLink}\fs8\cf0\f0\charscalex100 {\uc1\u8482X}\fs16\cf0\f0\charscalex100 {
air\uc1\u64258X ow control system; internal exhaust damper; and}\par\pard\li226
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determined forward-curved fans}\par\pard\li226\ri0\sl-280\slmult0 \fs16\cf0\f0\
charscalex100 {for each model size/width. CellGard ES}\fs8\cf0\f0\charscalex100
{\uc1\u8482X}\fs16\cf0\f0\charscalex100 { Biological Safety Cabinets}\par\pard\l
i226\ri0\sl-280\slmult0 \fs16\cf0\f0\charscalex100 {provide long-term reliabilit
y; outstanding performance; superior}\par\pard\li226\ri0\sl-293\slmult0 \fs16\cf
0\f0\charscalex100 {quality; and cost saving technologies.}\par\pard\li226\ri0\s
l-213\slmult0 \fs18\cf0\par\pard\li226\ri0\sl-200\slmult0 \fs16\cf0\f0\charscale
x100 {Our dedication to quality, performance, service, and customer}\par\pard\li
226\ri0\sl-280\slmult0 \fs16\cf0\f0\charscalex100 {satisfaction, makes NuAire}\f
s8\cf0\f0\charscalex100 {}\fs16\cf0\f0\charscalex100 { the perfect choice - a rea
l Value}\par\pard\li1586\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li1586\ri0\sl-213
\slmult0 \fs18\cf0\par\pard\li1586\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li1586\
ri0\sl-213\slmult0 \fs18\cf0\par\pard\li1586\ri0\sl-213\slmult0 \fs18\cf0\par\pa
rd\li1586\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li1586\ri0\sl-160\slmult0 \fs12\
cf3\f0\charscalex100 {NuAire, Inc.}\fs6\cf3\f0\charscalex100 {}\fs12\cf3\f0\chars
calex100 { | 2100 Fernbrook Lane | Plymouth, MN 55447}\par\pard\li2133\ri0\sl-16
0\slmult0 \fs12\cf3\f0\charscalex100 {Ph: 1.800.328.3352 | Fx: 763.553.0459}\par
\column\pard\li1640\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li1640\ri0\sl-213\slmu
lt0 \fs18\cf0\par\pard\li1640\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li1640\ri0\s
l-346\slmult0 \fs18\cf3\f0\charscalex100 {www.}\fs18\cf3\f0\charscalex100\b {nua
ire}\b0 \fs18\cf3\f0\charscalex100 {.com}\par\pard\li2360\ri0\sl-213\slmult0 \fs
18\cf0\par\pard\li2360\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li2360\ri0\sl-213\s
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\sl-186\slmult0 \fs16\cf1\f0\charscalex100 {Research Reports}\par\pard\li120\ri0
\sl-213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl-213\slmult0 \fs18\cf0\par\pard\l

i120\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl-213\slmult0 \fs18\cf0\pa
8\cf0\par\pard\li120\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl-213\slmu
lt0 \fs18\cf0\par\pard\li120\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li120
\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl-213\slmult0 \fs18\cf0\par\pa
rd\li120\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl-213\slmult0 \fs18\cf
0\par\pard\li120\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl-213\slmult0
\fs18\cf0\par\pard\li120\ri0\sl-186\slmult0 \fs12\cf0\f0\charscalex100\b {Figure
2. CXCL12-GL and GL have comparable }\b0 \par\pard\li120\ri0\sl-186\slmult0 \fs
10\cf0\f0\charscalex100\b {bioluminescence emission spectra.}\b0 \fs12\cf0\f0\ch
arscalex100 { CXCL12-GL }\par\pard\li120\ri0\sl-186\slmult0 \fs16\cf0\f0\charsca
lex100 {and GL from cell culture supernatants were in}\fs16\cf0\f0\charscalex100
{-}\par\pard\li120\ri0\sl-186\slmult0 \fs14\cf0\f0\charscalex100 {cubated with
coelenterazine, and then emission }\par\pard\li120\ri0\sl-186\slmult0 \fs14\cf0\
f0\charscalex100 {spectra were recorded from both proteins. Data }\par\pard\li12
0\ri0\sl-186\slmult0 \fs16\cf0\f0\charscalex100 {are representative of 3 indepen
dent analyses.}\par\column\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri
0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-453\slmult0 \fs24\cf0\f0\charscal
ex100\b {A}\b0 \par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-21
3\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\s
l-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\r
i0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\l
i0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pa
rd\li0\ri0\sl-466\slmult0 \fs24\cf0\f0\charscalex100\b {C}\b0 \par\column\pard\l
i0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pa
rd\li0\ri0\sl-453\slmult0 \fs24\cf0\f0\charscalex100\b {B}\b0 \par\pard\li0\ri0\
sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\
ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\
li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\p
ard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\p
ar\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-466\slmult0 \fs24\c
f0\f0\charscalex100\b {D}\b0 \par\pard\sect\sectd\sbknone\pgwsxn11880\pghsxn1556
0\marglsxn666\margrsxn133\cols2\colno1\colw3600\colsr-0\colno2\colw7480\pard\li1
20\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl-213\slmult0 \fs18\cf0\par\
pard\li120\ri0\sl-320\slmult0 \fs18\cf0\f0\charscalex100 {were detected with a 1
:2000 dilution of }\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100
{secondary anti-rabbit antibody conju}\fs20\cf0\f0\charscalex100 {-}\par\par
d\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {gated to horseradish pero
xidase (Sigma-}\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {Al
drich). Blots were developed with ECL}\par\pard\li120\ri0\sl-253\slmult0 \fs16\c
f0\f0\charscalex100 {Plus reagent (GE Healthcare Life Sciences, }\par\pard\li120
\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {Piscataway, NJ, USA). Membranes
then }\par\pard\li120\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {were stripp
ed and re-probed for total levels }\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\
f0\charscalex100 {of AKT using 1:500 and 1:2000 dilutions}\par\pard\li120\ri0\sl
-253\slmult0 \fs18\cf0\f0\charscalex100 {of primary (Cell Signaling) and seconda
ry}\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {antibodies, re
spectively.}\par\pard\li120\ri0\sl-240\slmult0 \fs20\cf2\f0\charscalex100 {Stati
stics}\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {Data were p
lotted as mean values with }\par\pard\li120\ri0\sl-253\slmult0 \fs16\cf0\f0\char
scalex100 {standard error of the mean (}\fs16\cf0\f0\charscalex100 {SEM}\fs16\cf
0\f0\charscalex100 {). Pairs of }\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0
\charscalex100 {data were analyzed by two-tailed paired }\par\pard\li120\ri0\sl280\slmult0 \fs20\cf0\f0\charscalex100 {t}\fs20\cf0\f0\charscalex100 {-test to d
etermine statistically significant}\par\pard\li120\ri0\sl-280\slmult0 \fs18\cf0\
f0\charscalex100 {differences (}\fs18\cf0\f0\charscalex100 {P}\fs18\cf0\f0\chars
calex100 { < 0.05) (GraphPad Prism, }\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf
0\f0\charscalex100 {La Jolla, CA, USA).}\par\pard\li120\ri0\sl-346\slmult0 \fs28
\cf2\f0\charscalex100 {Results}\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf2\f0\c

harscalex100 {CXCL12-}\fs20\cf2\f0\charscalex100 {GL}\fs20\cf2\f0\charscalex100
{ fusion protein is secreted}\par\pard\li120\ri0\sl-240\slmult0 \fs20\cf2\f0\cha
rscalex100 {and activates CXCR4 signaling}\par\pard\li120\ri0\sl-253\slmult0 \fs
16\cf0\f0\charscalex100 {Chemokine CXCL12 binds to CXCR4 and }\par\pard\li120\ri
0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {CXCR7, two receptors that are emerg
ing as }\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {key regul
ators of cancer and other disease}\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f
0\charscalex100 {processes (23\uc1\u8211X25). To develop a biolu}\fs20\cf0\f0\ch
arscalex100 {-}\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {mi
nescent chemokine probe for quanti}\fs20\cf0\f0\charscalex100 {-}\par\pard\li120
\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {fying binding to CXCR4 and CXCR7
, we }\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {fused the C
-terminus of CXCL12 to the}\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\chars
calex100 {N-terminus of GL, removing the native }\par\pard\li120\ri0\sl-253\slmu
lt0 \fs18\cf0\f0\charscalex100 {secretion signal from GL. This design }\par\pard
\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {strategy maintains the sec
retion signal}\par\pard\li120\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {for
CXCL12 and an unfused N-terminus}\par\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f
0\charscalex100 {of the chemokine, which is critical for }\par\pard\li120\ri0\sl
-253\slmult0 \fs18\cf0\f0\charscalex100 {binding to CXCR4 (26). Removing the }\p
ar\pard\li120\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {secretion signal fr
om GL also has been }\par\pard\li120\ri0\sl-253\slmult0 \fs16\cf0\f0\charscalex1
00 {reported to increase bioluminescence from }\par\pard\li120\ri0\sl-253\slmult
0 \fs18\cf0\f0\charscalex100 {this enzyme (15).}\par\pard\li360\ri0\sl-253\slmul
t0 \fs18\cf0\f0\charscalex100 {To establish that CXCL12-GL is }\par\pard\li120\r
i0\sl-253\slmult0 \fs16\cf0\f0\charscalex100 {secreted from cells, we stably tra
nsduced }\par\column\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-2
13\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-373\slmult0 \fs12\cf0\f0\charscalex100\
b {Figure 3. Effects of temperature, NaCl, and pH on bioluminescence of CXCL12 a
nd GL.}\b0 \fs14\cf0\f0\charscalex100 { (A) CXCL12-GL }\par\pard\li0\ri0\sl-186\
slmult0 \fs16\cf0\f0\charscalex100 {and GL were incubated at various temperature
s ranging 37\uc1\u8211X65C before quantifying biolumines}\fs16\cf0\f0\charscalex1
00 {-}\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\charscalex100 {cence. Data a
re presented as mean values for luminescence of each enzyme relative to activity
}\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\charscalex100 {at 37C. (B-D) CXCL
12-GL and GL were incubated with varying concentrations of NaCl (B) or in }\par\
pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\charscalex100 {solutions of different p
H prepared in phosphate (C) or tris (D) buffers prior to quantifying biolumi}\fs
16\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-186\slmult0 \fs16\cf0\f0\charsca
lex100 {nescence. Data are graphed as mean values for luminescence normalized fo
r each enzyme to 0 mM }\par\pard\li0\ri0\sl-200\slmult0 \fs16\cf0\f0\charscalex1
00 {NaCl (B), or pH 7.4 (C, D). Error bars denote }\fs12\cf0\f0\charscalex100 {SE
M}\fs16\cf0\f0\charscalex100 { in all panels (}\fs16\cf0\f0\charscalex100 {n}\fs
16\cf0\f0\charscalex100 { = 4 per condition, representative }\par\pard\li0\ri0\s
l-200\slmult0 \fs16\cf0\f0\charscalex100 {of 3 independent experiments for each
condition). *,}{ }\fs16\cf0\f0\charscalex100 {P}\fs16\cf0\f0\charscalex100 { < 0
.05; **,}{ }\fs16\cf0\f0\charscalex100 {P}\fs16\cf0\f0\charscalex100 { < 0.01.}\
par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-306\slmult0 \*\tx3
480\fs20\cf0\f0\charscalex100 {293T cells with a lentiviral vector that }\tab \f
s20\cf0\f0\charscalex100 {and determined activation of AKT, a }\par\pard\li
0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {constitutively produce
s this protein. After}\tab \fs18\cf0\f0\charscalex100 {known downstream effector
of CXCL12-}\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100
{culturing these cells overnight in serum-}\tab \fs20\cf0\f0\charscalex100 {CXC
R4 signaling}\fs18\cf0\f0\charscalex100 {(28). Relative to unfused }\par\pard\li
0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {free medium, we collec
ted supernatants and }\tab \fs18\cf0\f0\charscalex100 {CXCL12, cells treated wit
h CXCL12-GL }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\charscalex10
0 {quantified amounts of CXCL12 and GL }\tab \fs20\cf0\f0\charscalex100 {had com
parable activation of AKT in }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf

0\f0\charscalex100 {activity by ELISA and luminescence, respec}\fs18\cf0\f0\char
scalex100 {-}\tab \fs18\cf0\f0\charscalex100 {231-CXCR4 cells, as measured by ph
ospho}\fs18\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\f
s18\cf0\f0\charscalex100 {tively. In three independent preparations of }\tab \fs
20\cf0\f0\charscalex100 {rylation at serine 473 (Figure 1C). In }\par\pard\li0\r
i0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {CXCL12-GL, amounts of CXC
L12 corre}\fs18\cf0\f0\charscalex100 {-}\tab \fs20\cf0\f0\charscalex100 {additio
n, Western blotting showed that }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs18
\cf0\f0\charscalex100 {lated directly with bioluminescence (Figure }\tab \fs20\c
f0\f0\charscalex100 {treatment with CXCL12-GL produced a }\par\pard\li0\ri0\sl-2
53\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {1A). Based on measurements of bi
olumi}\fs18\cf0\f0\charscalex100 {-}\tab \fs18\cf0\f0\charscalex100 {similar ext
ent of AKT phosphorylation as}\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf
0\f0\charscalex100 {nescence, as little as 0.05 ng CXCL12 could }\tab \fs18\cf0\
f0\charscalex100 {that from comparable amounts of synthetic }\par\pard\li0\ri0\s
l-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {be detected. These data estab
lish biolumi}\fs18\cf0\f0\charscalex100 {-}\tab \fs18\cf0\f0\charscalex100 {CXCL
12. By comparison, neither CXCL12}\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs1
8\cf0\f0\charscalex100 {nescence as a sensitive, quantitative assay }\tab \fs18\
cf0\f0\charscalex100 {nor CXCL12-GL altered phosphorylation }\par\pard\li0\ri0\s
l-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {for levels of CXCL12-GL.}\tab
\fs18\cf0\f0\charscalex100 {of AKT in 231-control or 231-CXCR7 cells }\par\pard
\li240\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {To establish that
CXCL12-GL }\tab \fs18\cf0\f0\charscalex100 {(data not shown). Results for 231-c
ontrol }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {re
mained biologically active, we directly }\tab \fs18\cf0\f0\charscalex100 {and 23
1-CXCR7 cells are consistent with}\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs2
0\cf0\f0\charscalex100 {compared cell signaling in response to }\tab \fs20\cf0\f
0\charscalex100 {the lack of CXCR4 expression observed }\par\pard\li0\ri0\sl-253
\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {supernatants from 293T cells produ
cing}\tab \fs18\cf0\f0\charscalex100 {in 231-control cells by flow cytometry and
}\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {CXCL12-GL
or unfused CXCL12. We}\tab \fs20\cf0\f0\charscalex100 {failure of CXCL12-CXCR7
binding to }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100
{used human MDA-MB-231 breast cancer}\tab \fs18\cf0\f0\charscalex100 {activate
AKT in most cell lines (7). Collec}\fs18\cf0\f0\charscalex100 {-}\par\pard\li0\r
i0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {cells stably transduced w
ith CXCR4-GFP }\tab \fs20\cf0\f0\charscalex100 {tively, these studies show that
CXCL12 }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {(2
31-CXCR4), CXCR7 (231-CXCR7) or }\tab \fs18\cf0\f0\charscalex100 {remains functi
onal when fused to GL.}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex1
00 {GFP alone (231-control) for this analysis }\par\pard\li0\ri0\sl-253\slmult0
\*\tx3480\fs20\cf0\f0\charscalex100 {(Figure 1B). We note that 231-CXCR7}\tab \f
s20\cf2\f0\charscalex100 {Emission spectrum of CXCL12-GL}\par\pard\li0\ri0\sl-25
3\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {cells express relatively lower am
ounts of }\tab \fs20\cf0\f0\charscalex100 {To determine effects of CXCL12 on }\p
ar\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\charscalex100 {this chemoki
ne on the cell surface than }\tab \fs20\cf0\f0\charscalex100 {bioluminescence fr
om GL, we measured }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\chars
calex100 {cells transduced with CXCR4, likely due }\tab \fs18\cf0\f0\charscalex1
00 {emission spectra of CXCL12-GL and GL}\par\pard\li0\ri0\sl-253\slmult0 \*\tx3
480\fs18\cf0\f0\charscalex100 {to relatively greater intracellular expression }\
tab \fs18\cf0\f0\charscalex100 {at wavelengths ranging 300\uc1\u8211X700 nm. The
}\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs18\cf0\f0\charscalex100 {of transd
uced and endogenous CXCR7 in}\tab \fs18\cf0\f0\charscalex100 {emission spectrum
from CXCL12-GL was }\par\pard\li0\ri0\sl-253\slmult0 \*\tx3480\fs20\cf0\f0\chars
calex100 {cells (7,27).}\tab \fs20\cf0\f0\charscalex100 {comparable to that prod
uced by unfused }\par\pard\li240\ri0\sl-280\slmult0 \*\tx3480\fs18\cf0\f0\charsc
alex100 {We treated various 231 cell lines with }\tab \fs20\cf0\f0\charscalex100
{GL with a peak emission of}{ }\fs20\cf0\f0\charscalex100 {\uc1\u8764X}\fs20\cf

0\f0\charscalex100 {500 nm}\par\pard\li0\ri0\sl-266\slmult0 \*\tx3480\fs20\cf0\f
0\charscalex100 {\uc1\u8764X}\fs20\cf0\f0\charscalex100 {25 ng/mL CXCL12-GL or C
XCL12}\tab \fs18\cf0\f0\charscalex100 {(Figure 2). The peak wavelength is slight
ly }\par\pard\sect\sectd\sbknone\pgwsxn11880\pghsxn15560\marglsxn666\margrsxn133
\cols3\colno1\colw4893\colsr-0\colno2\colw3600\colsr-0\colno3\colw2586\pard\li12
0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li120\ri0\sl-360\slmult0 \fs18\cf1\f0\ch
arscalex100 {Vol. 47 | No. 1 | 2009}\par\column\pard\li0\ri0\sl-640\slmult0 \fs3
6\cf1\f0\charscalex100 {628}\par\column\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\pa
r\pard\li0\ri0\sl-360\slmult0 \fs16\cf1\f0\charscalex100 {www.BioTechniques.com}
\par\pard\sect\sectd\sbknone\pgwsxn11880\pghsxn15560\marglsxn666\margrsxn133\par
d\sect\sectd\sbkpage
7;32768}}
7;32768}}

7;32768}}
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i440\ri0\sl-466\slmult0 \fs24\cf0\f0\charscalex100\b {A}\b0 \par\column\pard\li0
\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\pard
\li0\ri0\sl-466\slmult0 \fs24\cf0\f0\charscalex100\b {B}\b0 \par\column\pard\li1
880\ri0\sl-186\slmult0 \fs16\cf1\f0\charscalex100 {Research Reports}\par\pard\li
0\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li0\ri0\sl-440\slmult0 \fs18\cf0\f0\char
scalex100 {greater than the 480-nm peak wavelength }\par\pard\li0\ri0\sl-253\slm
ult0 \fs18\cf0\f0\charscalex100 {reported previously for GL (14), potentially }\
par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {due to different ass
ay conditions. Never}\fs18\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-253\slmu
lt0 \fs18\cf0\f0\charscalex100 {theless, these data establish that fusion of}\pa
r\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {CXCL12 to GL does not
alter biolumines}\fs18\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-253\slmult0
\fs18\cf0\f0\charscalex100 {cence produced by the enzyme.}\par\pard\li0\ri0\sl-2
40\slmult0 \fs20\cf2\f0\charscalex100 {Temperature and pH stability of}\par\pard
\li0\ri0\sl-240\slmult0 \fs20\cf2\f0\charscalex100 {CXCL12-GL relative to GL}\pa
r\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {To further analyze
and validate}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {CXCL1
2-GL, we investigated effects of }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\
charscalex100 {temperature, pH, and NaCl concentration }\par\pard\li0\ri0\sl-253
\slmult0 \fs20\cf0\f0\charscalex100 {on enzymatic activity of CXCL12-GL }\par\pa
rd\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {relative to unfused GL. Bo
th CXCL12-GL }\par\pard\sect\sectd\sbknone\pgwsxn11880\pghsxn15560\marglsxn666\m
argrsxn133\cols2\colno1\colw7320\colsr-0\colno2\colw3760\pard\li386\ri0\sl-306\s
lmult0 \fs12\cf0\f0\charscalex100\b {Figure 4. Chemokine receptors CXCR4 and CXC
R7 enhance cell-associated CXCL12-GL.}\b0 \fs16\cf0\f0\charscalex100 { (A) 231 b
reast }\par\pard\li386\ri0\sl-266\slmult0 \fs14\cf0\f0\charscalex100 {cancer cel
l lines were incubated with}{ }\fs18\cf0\f0\charscalex100 {\uc1\u8764X}\fs14\cf0
\f0\charscalex100 {3 ng/mL CXCL12-GL for 2 h. GL supernatants were added }\par\p
ard\li386\ri0\sl-200\slmult0 \fs16\cf0\f0\charscalex100 {to parallel cultures of
cells. Data are presented as mean values for photons +}\fs12\cf0\f0\charscalex1
00 {SEM}\fs16\cf0\f0\charscalex100 { (}\fs16\cf0\f0\charscalex100 {n}\fs16\cf0\f
0\charscalex100 { = 4 per condi}\fs16\cf0\f0\charscalex100 {-}\par\pard\li386\ri
0\sl-200\slmult0 \*\tx4106\*\tx5080\fs14\cf0\f0\charscalex100 {tion, representat
ive of 5 independent experiments). *,}\tab \fs14\cf0\f0\charscalex100 {P}\fs14\c
f0\f0\charscalex100 { < 0.01; **,}\tab \fs14\cf0\f0\charscalex100 {P}\fs14\cf0\f
0\charscalex100 { < 0.005. (B) 231-CXCR7 }\par\pard\li386\ri0\sl-186\slmult0 \fs
14\cf0\f0\charscalex100 {and 231-control cells were incubated with 30 ng/mL CXCL
12-GL in the presence of increasing }\par\pard\li386\ri0\sl-186\slmult0 \fs14\cf
0\f0\charscalex100 {concentrations of synthetic CXCL12 as described in A. Data a
re presented as mean values }\fs10\cf0\f0\charscalex100 {SEM}\fs14\cf0\f0\charsca
lex100 { of }\par\pard\li386\ri0\sl-186\slmult0 \fs14\cf0\f0\charscalex100 {lumi
nescence relative to cell-associated CXCL12-GL in the absence of synthetic CXCL1
2 competitor }\par\pard\li386\ri0\sl-200\slmult0 \fs16\cf0\f0\charscalex100 {(}\
fs16\cf0\f0\charscalex100 {n}\fs16\cf0\f0\charscalex100 { = 4 per condition, rep
resentative of 2 independent experiments).}\par\pard\li1533\ri0\sl-213\slmult0 \
fs18\cf0\par\pard\li1533\ri0\sl-453\slmult0 \fs24\cf0\f0\charscalex100\b {A}\b0
\par\pard\li440\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li440\ri0\sl-213\slmult0 \
fs18\cf0\par\pard\li440\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li440\ri0\sl-213\s
lmult0 \fs18\cf0\par\pard\li440\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li440\ri0\
sl-213\slmult0 \fs18\cf0\par\pard\li440\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li
440\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li440\ri0\sl-213\slmult0 \fs18\cf0\par
\pard\li440\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li440\ri0\sl-213\slmult0 \fs18
\cf0\par\pard\li440\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li440\ri0\sl-213\slmul
t0 \fs18\cf0\par\pard\li440\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li440\ri0\sl-2
80\slmult0 \*\tx4160\fs24\cf0\f0\charscalex100\b {B}\b0 \tab \fs24\cf0\f0\charsc
alex100\b {C}\b0 \par\pard\li346\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li346\ri0
i346\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li346\ri0\sl-213\slmult0 \fs18\cf0\pa
8\cf0\par\pard\li346\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li346\ri0\sl-213\slmu
lt0 \fs18\cf0\par\pard\li346\ri0\sl-213\slmult0 \fs18\cf0\par\pard\li346\ri0\sl213\slmult0 \fs18\cf0\par\pard\li346\ri0\sl-266\slmult0 \fs12\cf0\f0\charscalex1
00\b {Figure 5. Pharmacologic inhibition of CXCL12-GL binding.}\b0 \fs16\cf0\f0\
charscalex100 { (A) 231-CXCR7 cells were incubated with}\par\pard\li346\ri0\sl-1
86\slmult0 \fs16\cf0\f0\charscalex100 {various concentrations of small-molecule
inhibitors of CXCR4 (AMD3100) or CXCR7 (CCX733,}\par\pard\li346\ri0\sl-186\slmul
t0 \fs16\cf0\f0\charscalex100 {CCX754) or vehicle control (NT) for 30 min prior
to adding 5 ng/mL CXCL12-GL. Cells were incu-}\par\pard\li346\ri0\sl-186\slmult0
\fs14\cf0\f0\charscalex100 {bated for an additional 2 h before quantifying biol
uminescence in living cells. Data are presented }\par\pard\li346\ri0\sl-186\slmu
lt0 \fs16\cf0\f0\charscalex100 {as mean values of luminescence relative to cells
treated with vehicle only (NT). Error bars denote}\par\pard\li346\ri0\sl-200\sl
mult0 \fs16\cf0\f0\charscalex100 {}\fs12\cf0\f0\charscalex100 {SEM}\fs16\cf0\f0\c
harscalex100 {.}{ }\fs16\cf0\f0\charscalex100 {Inset shows bioluminescence image
of the 96-well plate (}\fs16\cf0\f0\charscalex100 {n}\fs16\cf0\f0\charscalex100
{ = 3 per condition, representa}\fs16\cf0\f0\charscalex100 {-}\par\pard\li346\r
i0\sl-186\slmult0 \fs16\cf0\f0\charscalex100 {tive of 2 independent experiments)
. (B) Cell membrane expression of CXCR7 on MCF-7 human}\par\pard\li346\ri0\sl-18
6\slmult0 \fs16\cf0\f0\charscalex100 {breast cancer cells was determined by flow
cytometry as described in Figure 1. Open plot repre-}\par\pard\li346\ri0\sl-186
\slmult0 \fs16\cf0\f0\charscalex100 {sents staining with isotype control antibod
y, while the filled plot represents staining for CXCR7.}\par\pard\li346\ri0\sl-1
86\slmult0 \fs16\cf0\f0\charscalex100 {(C) MCF-7 cells were pre-treated with inc

reasing concentrations of CXCR7 inhibitor CCX733 and}\par\pard\li346\ri0\sl-186\
slmult0 \fs16\cf0\f0\charscalex100 {then incubated with CXCL12-GL as described i
n panel A. Data are presented as mean values of}\par\pard\li346\ri0\sl-200\slmul
t0 \fs16\cf0\f0\charscalex100 {luminescence relative to cells incubated with no
CCX733. Error bars denote}{ }\fs12\cf0\f0\charscalex100 {SEM}\fs16\cf0\f0\charsc
alex100 { (}\fs16\cf0\f0\charscalex100 {n}\fs16\cf0\f0\charscalex100 { = 4 per c
ondi}\fs16\cf0\f0\charscalex100 {-}\par\pard\li346\ri0\sl-186\slmult0 \fs16\cf0\
f0\charscalex100 {tion, representative of 2 independent experiments).}\par\colum
n\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {and GL retained near p
eak biolumines}\fs20\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \f
s20\cf0\f0\charscalex100 {cence after incubation for 1 h at temper}\fs20\cf0\f0\
charscalex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {at
ures ranging 37\uc1\u8211X50C (Figure 3A). At }\par\pard\li0\ri0\sl-253\slmult0 \
fs20\cf0\f0\charscalex100 {higher temperatures, activities of both }\par\pard\li
0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {proteins decreased substantiall
y, although }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {loss o
f activity was relatively greater for }\par\pard\li0\ri0\sl-280\slmult0 \fs20\cf
0\f0\charscalex100 {CXCL12-GLattemperaturesupto65C(}\fs20\cf0\f0\charscalex100 {P
}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {< 0.05). Reduced s
tability of CXCL12-GL }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex1
00 {at elevated temperatures may be due to }\par\pard\li0\ri0\sl-253\slmult0 \fs
20\cf0\f0\charscalex100 {denaturation of the CXCL12 component}\par\pard\li0\ri0\
sl-253\slmult0 \fs18\cf0\f0\charscalex100 {of the fusion protein with associated
loss of }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {activity
of fused GL. Nevertheless, fusion}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\
charscalex100 {to CXCL12 does not substantially impair}\par\pard\li0\ri0\sl-253\
slmult0 \fs20\cf0\f0\charscalex100 {thermal stability of GL.}\par\pard\li240\ri0
\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {GL is reported to be dependent upon
}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {sodium for peak ac
tivity (www.nanolight.}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex1
00 {com/proteins/Luciferase_Data.ppt#23 ).}\par\pard\li0\ri0\sl-253\slmult0 \fs1
8\cf0\f0\charscalex100 {To quantify effects of CXCL12 on sodium }\par\pard\li0\r
i0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {dependence of GL, we incubated
}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {CXCL12-GL and GL
in concentrations of }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex10
0 {NaCl ranging 0\uc1\u8211X1 M. For CXCL12-GL,}\par\pard\li0\ri0\sl-253\slmult0
\fs20\cf0\f0\charscalex100 {peak bioluminescence increased from }\par\pard\l
i0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {0 mM to 200 mM NaCl and did no
t vary}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {significantl
y at higher concentrations up to }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\
charscalex100 {1 M (Figure 3B). Similar to CXCL12-GL,}\par\pard\li0\ri0\sl-253\s
lmult0 \fs20\cf0\f0\charscalex100 {bioluminescence from unfused GL also }\par\pa
rd\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {increased as NaCl concentr
ations increased }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {t
o 200 mM. However, bioluminescence }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f
0\charscalex100 {from GL decreased significantly relative }\par\pard\li0\ri0\sl253\slmult0 \fs20\cf0\f0\charscalex100 {to CXCL12-GL at \uc1\u8805X400 mM N
aCl}\par\pard\li0\ri0\sl-280\slmult0 \fs20\cf0\f0\charscalex100 {(}\fs20\cf0\f0\
charscalex100 {P}\fs20\cf0\f0\charscalex100 { < 0.01).}\par\pard\li240\ri0\sl-25
3\slmult0 \fs16\cf0\f0\charscalex100 {GL also is reported to maintain activity }
\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {across a wide range
of pH (www.nanolight.}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex1
00 {com/proteins/Luciferase_Data.ppt#23 ).}\par\pard\li0\ri0\sl-253\slmult0 \fs2
0\cf0\f0\charscalex100 {To establish effects of CXCL12 on pH }\par\pard\li0\ri0\
sl-253\slmult0 \fs20\cf0\f0\charscalex100 {stability of GL, we compared biolumi}
\fs20\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\char
scalex100 {nescence from CXCL12-GL and GL in }\par\pard\li0\ri0\sl-253\slmult0 \
fs18\cf0\f0\charscalex100 {either phosphate- or tris-buffered solutions}\par\par
d\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {of various pH. Relative to
unfused GL, }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {CXCL12

-GL produced greater biolu}\fs20\cf0\f0\charscalex100 {-}\par\pard\li0\ri0\sl-25
3\slmult0 \fs20\cf0\f0\charscalex100 {minescence in acidic phosphate- or tris-}\
par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100 {buffered solutions (
Figure 3, C and D). }\par\pard\li0\ri0\sl-253\slmult0 \fs20\cf0\f0\charscalex100
{In phosphate buffer, CXCL12-GL had }\par\pard\li0\ri0\sl-280\slmult0 \fs20\cf0
\f0\charscalex100 {relatively constant activity from pH}{ }\fs20\cf0\f0\charscal
ex100 {\uc1\u8764X}\fs20\cf0\f0\charscalex100 {4.0}\par\pard\li0\ri0\sl-280\slmu
lt0 \fs20\cf0\f0\charscalex100 {to pH }{ }\fs20\cf0\f0\charscalex100 {\uc1\u876
4X}\fs20\cf0\f0\charscalex100 {11.0, while bioluminescence}\par\pard\li0\ri0\s
l-253\slmult0 \fs20\cf0\f0\charscalex100 {from GL dropped significantly at pH 6.
0 }\par\pard\li0\ri0\sl-280\slmult0 \fs20\cf0\f0\charscalex100 {and below (}\fs2
0\cf0\f0\charscalex100 {P}\fs18\cf0\f0\charscalex100 { < 0.01) (Figure 3C). Neit
her }\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charscalex100 {enzyme had det
ectable bioluminescence at}\par\pard\li0\ri0\sl-253\slmult0 \fs18\cf0\f0\charsca
lex100 {pH 3.0 in phosphate buffer. GL had slightly }\par\pard\li0\ri0\sl-253\sl
mult0 \fs16\cf0\f0\charscalex100 {greater activity in basic phosphate solutions,
}\par\pard\sect\sectd\sbknone\pgwsxn11880\pghsxn15560\marglsxn666\margrsxn133\c
ols3\colno1\colw4893\colsr-0\colno2\colw3840\colsr-0\colno3\colw2346\pard\li360\
ri0\sl-213\slmult0 \fs18\cf0\par\pard\li360\ri0\sl-360\slmult0 \fs18\cf1\f0\char
scalex100 {Vol. 47 | No. 1 | 2009}\par\column\pard\li0\ri0\sl-640\slmult0 \fs36\
cf1\f0\charscalex100 {629}\par\column\pard\li0\ri0\sl-213\slmult0 \fs18\cf0\par\
pard\li0\ri0\sl-346\slmult0 \fs16\cf1\f0\charscalex100 {www.BioTechniques.com}\p
ar}

Bioluminescent CXCL12 Fusion Protein

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Bioluminescent CXCL12 Fusion Protein

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0\f0\charscalex100 {and quantification (14). Bioluminescence }\par\pard\li0\ri0\

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