You are on page 1of 28

Reproductive Tract Sarcomas in E2F-1-/-

Females and Males Cell, 85, 537–548,1996


Lung Adenocarcinomas
in E2F-1-/- Animals
Cell, 85, 537–548,1996

Tumor mass
E2F-1

axial lymph node

spleen

mesenteric nodes

Cell, 85, 537–548,1996


CDK inhibitors

2002, 3:11-20
Nature 408, 307 - 310 (2000)
Nature 408, 307 - 310 (2000)
Nature 408, 307 - 310 (2000)
Cell. 2001 Sep 7;106(5):531-4.
Seminars in Cancer Biology
13:41-47, 2003
SCF ligases controlled the G1 to S transition,
whereas APC ligases controlled the onset and exit from mitosis.
Wrong!!

APC: 13 core components, and two specificity factors—Cdc20 and Cdh1


The SCF (Skp-Cullin-F box) family of Ubls:
consist of a number of core components—Skp1, Cul1, Roc1—
in complex with a unique “F box” protein that confers substrate specificity
F box proteins have at least two functional domains—an ~40 amino acid
F box domain that binds Skp1 and tethers the F box protein to the core
SCF components, and a protein-protein interaction domain (often a series
of leucine-rich repeats or WD40 domains) that specifically binds substrate
proteins. A vast collection of F box proteins, each with different substrate
specificity, exists in mammals, with proteins such as β-TrCP, hCDC4,
and Skp2
Cancer Cell, 5:305, 2004
Cdc20: synthesized late in G2 and coordinates events required for
the onset of mitosis through to anaphase.
Cdh1: becomes active toward the end of anaphase and ultimately brings
about the end of mitosis by targeting destruction of Cdc20, as well
as mitotic cyclins and other regulators.

Nature 424:194, 2004


Nature 424:194, 2004
Molecular Cell, 22:1-4, 2006
Molecular Cell, 22:1-4, 2006
Signals cooperate to keep APC/Ccdh1 inactive from G1/S
until late mitosis:

4. CDKs: Phosphorylation of Cdh1leads to dissociation from APC/C


5. Emi1: inhibitor of APC/C; trans-activated by E2F (Hsu et al.,
2002, Nat.Cell Biol. 4:358-366)
• APC/Ccdh1 : degrades Cdh1 and its ubiqutin conjugating enzyme
Ubc10 (Lukas and Bartek, 2004, Nature 432, 564-567)
Cdc25A is regulated at transcriptional and post-translational levels.
The transcription factors E2F1, E2F4, and c-Myc promote the
expression of Cdc25A in mid- to late G1 (Galaktionov et al., 1996;
Vigo et al., 1999)

Cdc25A has two major peaks of accumulation during cell-cycle


progression, one in G1 and the other in S/G2 (Bernardi et al., 2000).

Oncogene (2005) 24, 299–305.


During S phase and G2, the level of Cdc25A is regulated by the ubiquitin
ligase SCF (Skp1/Cullin/F-box) (Donzelli et al., 2002). The Cdc25A is
phosphorylated on Ser82 and Ser88, which mediate binding to the
SCF/beta-TrCP complex to promote ubiquitin ligation and Cdc25A
degradation (Busino et al., 2003). Another ubiquitin ligase APC/C
(anaphase promoting complex/cyclosome), in complex with the cdh1
subunit, regulates the level of Cdc25A at mitotic exit and during G1
(Donzelli et al., 2002). Residual Cdc25A remaining from mitosis is
degraded in G1 in response to APC-mediated ubiquitylation.
To promote the G1/S transition, transcription of cdc25A is enhanced,
and the APC is inactivated.

In response to DNA damage, Chk1 and Chk2 kinases phosphorylate


Ser123 on Cdc25A to initiate its ubiquitylation and proteosome-mediated
degradation (Mailand et al., 2000; Falck et al., 2001).
Oncogene (2005) 24, 299–305.
Absence of apparent phenotype in mice lacking Cdc25C protein
Phosphatase- Mol. Cell. Biol. 21: 3853−3861, 2001.

Normal cell cycle and checkpoint responses in mice and cells lacking
Cdc25B and Cdc25C protein phosphatases - Mol. Cell. Biol. 2005,
7:2853-60

The ATM-Chk2-Cdc25A checkpoint pathway guards against


radioresistant DNA synthesis.
Nature. 2001 Apr 12;410(6830):842-7.
Nature 2001,410(6830):842-7.
Nature 2001,
410(6830):842-7.
(Mt Chk2)
Nature 2001,
410(6830):842-7.
Nature 2001,
410(6830):842-7.
Cell, Vol 124, 367-380, 2006
Cell, Vol 124, 367-380, 2006