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The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 09

The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 09

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Published by Sri Harsha
The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 09
The Biology Of Cancer (2007) - Robert A. Weinberg - Ch. 09

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Published by: Sri Harsha on Jan 31, 2013
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08/09/2014

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Chapter 9
p53 and Apoptosis: Master Guardian and Executioner 
To
examine thecausesof
life
,
we
must first have recourse to death.Mary Shelley,
Frankenstein,
1831
There
cannot
however be the least
doubt
,that the higher organisms, as they are nowconstructed,contain within themselves thegerms of death.August Weissmann, philosopher of biology,
1889
M
etazoan organisms haveavital interest in eliminating defective or malfunctioning cells from their tissues. Responding
to
this need,
mammals
have implanted a loyal
watchman
in their cells. Within almost all cells in mammalian tissues, the p53 protein serves as the local representative of the organism's interests. p53
is
present on-site
to
ensure that the cell keeps its householdin order.
If
p53 receives information
about
metabolic disorder or genetic damage withina cell, it may arrest the advance of the cell through its grovvth-and-divisioncycle and, at the
same
time, orchestrate localized responses in
that
cell to facilitate the repair of damage.
If
p53 learns that metabolic
derangement
or damageto the genome
is
too severe to be cured,it may decide to emit signals thatawaken the cell's normally latent suicide
program-apoptosis.
The conse
quence
is
the rapid death of thecell.This results in the elimination of a cellwhose
continued
growth and division might otherwise pose a threat to theorganism's health
and
viability.
3
 
Chap
t
er
9:
p53
and
Apoptosis:
Master Guardian
andExecutioner
Figure
9.1
Large T
antigen
in
5V40
transformed
cells Antibodies that bindthe
SV40
large
T
(IT)
antigen
can be
used
to
detect
IT
in
the nucl
ei
of
SV40transformed tumor
cells
.
In
thepresent
case,
such
antibodieshave been
used
to
stainhuman mammaryepithelial cells(
MECs
)that weretransformed
by
introduction
of
the
SV40
early regionplus
two
othergenes. A similar imagewould
be
seen
if
such
antibodieswere
used
to
stain SV40-transformed mouse
cells.
IT
was detected
by
linking theseantibody molecules
to
peroxidaseenzyme, which generated the
dark
brown
spots.
In
this image
of
atumorxenograft,the transformed
MECs
formducts
(seen
in
cross
section), which
are
surrounded
by
normal stromal
cells
(light
bluenuclei).
(Courtesy
of
TA
Ince)
Theapoptoticprogram
that
may beactivatedby p53
is
built into the control circuitryofmostcellsthroughout the body. Apoptosisconsistsofaseries of dis tinctivecellular changesthat function to ensure the disappearance of
all
tracesofa cell, oftenwithin an
hour
of its initial activation. Thecontinuedpresence ofalatent
but
intactapoptotic machinery represents
an
ongoing threat to anincipientcancercell, since this machinery
is
poised to eliminatecellsthat are
en
route
to
becoming neoplastic. Thisexplainswhy p53 function
must
be disabledbefore a clone of pre-malignantcellsgains a sure
and
stable foothold withinatissue. Without a clear descriptionofp53 function
and
apoptosis,we have nohope of understanding a fundamental
component
of the process
that
leads tothecreationof virtually all types of
human
tumors.
9.1 Papovaviruses lead to the discovery
of
p53
When murine cells that have been transformed by the
SV40
DNA
tumor
virus areinjectedintoa mouse of identicalgeneticbackground
(Le
., a
syngeneic
host), the
immune
system of the host reacts by
mounting
a strong response; antibodiesare
made
that react with a nuclear protein that is present in the virus-transformedcells
and
is otherwise undetectable in normal mousecells(Figure 9.1).This protein, the large
tumor
(large
T,
LT)
antigen,
is
encodedby a region of theviralgenome that
is
alsoexpressedwhen this virus infects
and
multiplies withinmonkey kidney
cells-host
cellsthat permit a full infectious (lytic)cycleto pro ceedtocompletion (Section 3.4).Large T
is
amultifunctionalproteinthat
SV40
virus uses
to
perturb a
number
ofdistinct regulatory circuits within infected and transformedcells.Indeed, largeT wascitedin the previouschapterbecause of its ability to bind and thus func tionallyinactivatepRb (Sidebar8.4).Anti-large T sera harvested from mice and hamsters bearing SV40-induced tumors were used in 1979 toanalyzethe proteins present in SV40-transformedcells.The resulting immunoprecipitates contained both large T
and
anassociatedprotein thatexhibited an apparentmolec ularweightof
53
to
54
kilodaltons(Figure9.2). Antisera reactive with the p53proteinwerefound to detectthisprotein in mouseembryonal carcinomacells and,lateron,in a variety of
humanand
rodent
tumor
cellsthat
had
never beeninfected by
SV40.
However, monoclonal antibodies that recognized only large Timmunoprecipitated the53-to54-
kD
protein in virus-infected
but
not in uninfected cells.
8
 
Papovaviruses lead to the discovery
of
p53
Figure
9.2The
discovery
of
p53
Normal
BALB/c 3T3
mouse fibroblasts(3T3) transformedby SV40,
as
well
as
F9
mouseembryonalcarcinomacells, were exposed to
35S-
methionine, and resulting Iysateswereincubated
with
either normal hamster serum
(N)
or hamster antiserum
reactive
withSV40-transformed hamstercells(T
).
The
anti-tumor
se
rumimmunoprecipitated a protein
of
94
kD
fromviru
s-
infected
but not
uninfected 3T3
ce
ll
s.
In
addition, a second protein running slightly ahead
of
the 54-kD marker was immunoprecipitated from SV40-transformed94kD
3T3cells
but
not fromnormal
3T3
cells. Moreover,thissameprotein could
be
immunoprecipitated from
F9
cells,
whether
or
not
they hadbeen exposed to SV40
(arrow)
[These particular data,ontheirown,did 54kD
not
prove a physical association
of
SV40largeT(the94-kDprotein)with p53,
but
they didshow
that
p53wasa cellular protein
that
waspresentinelevated amountsin t
wo
t
ypes
of
transformed
ce
lls.](
Fr
om
D.I.Linzerand
A.J.
Levine,
Cell
17:43-52,
1979.)
Taken together, these observations indicated that the largeTproteinexpressedin SV40-transformedcells wastightly
bound
toanovel protein,which came
to
becalled p53. Antiserathatreacted withboth largeT
and
p53 detected p53in certain uninfectedcells,notably tumor cells thatweretransformed
by
non-viralmechanisms,suchas the
F9
embryonalcarcinoma
(Ee)
cells analyzed inFigure9.2. The latter observations indicated that p53was of cellularrather
than
viralorigin, aconclusionthat wasreinforcedby the reportinthe sameyearthat mouse cells transformed by exposure
to
a chemical carcinogenalsoexpressedp53. Thesevariouslinesof evidence suggested thatthe large Toncoproteinfunc tions,atleastinpart,
by
targetinghost-cell proteinsforbinding.(Thediscovery that large Tantigen
is
alsoableto
bind
pRb,theretinoblastoma protein, camesevenyearslater.) In theyears sincethese 1979discoveries,a
number
ofother
DNA
viruses
and
at leastone
RNA
virushave
been
found
to
specifyoncoproteinsthat associatewithp53orperturb its function(Table9.1).
(As
we willdiscusslaterinthischapter,
and
asis
apparent
fromthistable,thesevirusesalso target pRb
and
undertaketo blockapoptosis.)
Table 9.1
Tumor
viruses
that
perturb
pRb, p53,
and/or apoptotic
function
Virus Viral
protein
targeting
pRb
Viral
protein
targeting
p53
Viral
protein
targeting
apoptosis
SV40
Aderioviruslarge
T (LT)E1A
large
T (LT)E1B55KE1B19KaHPV
E7
E6
Polyom!!virus
Herpesvirus
saimiri
HHV-8 (KSHV)
HCMV
HTlV-1
large
TV cydihCK cyclinc
IEnf
Taxi.
large
T?
LANA-2
IE86
middle
T (MT)b
v-BcI~2d
v-BcI-2, d
v-FLlpe
vlCA,9 pUL37hEpstei n'-:Ba
rr
EBNA-1i LMP1i
aFunctions
like
BcI-2
toblockapoptosis.bActivates
PI3K
and
thus
AkVPKB
.(Relatedto D-type
cyclins.
dRelated
tocellular
BcI-2
anti-apoptotic protein.·Viral
caspase-8
(
FLlCE
)inhibitoryprotein; blocks
an early
step
in
the extrinsic apoptotic
cascade. 
flnteractswithand inhibits
pl07
and
poss
ibl
yp130;
may
also
target
pRb
fordegradation
in 
proteasomes.
9Binds
and
inhibits procaspase-8. hlnhibits theapoptoticpathwaybelow
caspas
e-8 and
beforecytoch
rome
c
relea
se. 
ilnducessynt
hesi
sof
cyclin
D2
and
bindsa
nd
inactivatesp16
1NK4
A. 
iLMPl facilitates
p52
NF-KB
activation
and
therebyinduces
expression
of
Bcl-2;
EBNA-l
acts
via
a cellularprotein,
USP7/HAUSP,
to
reduce p53
levels. 
3

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