Cancer cells exhibit abnormalities in cell-cycle control and in differentiation. This is due, at least partly, to the fact that most cancer cells harbor mutations that compromise the function of the retinoblastoma protein (pRB.) The best understood targets of pRB are members of the E2F cell-cycle regulatory transcription factor family. E2F, unfettered by pRB, can induce cellular proliferation but can also induce apoptosis. E2F is neutralized in S-phase by cyclin NCdk2. Short peptides ('RXL peptides') that block the interaction of cyclin A/cdk2 with E2F selectively kill transformed cells, perhaps due to the high levels of E2F that typify cancer cells compared to normal cells.
Specific aim 1 will be to confirm or refute the hypothesis that RXL peptides kill cells by preventing the neutralization of E2F by cyclin A/cdk2. Control of the G1/S transition by pRB is linked to its ability to repress E2F-responsive promoters, whereas control of differentiation is not. Two additional pRB interactors, EID1 and RBP2, might be linked to differentiation control. EID1 inhibits p300/CBP histone acetylase activity, blocks differentiation, and is rapidly polyubiquitinated as cell exit the cell-cycle. Understanding the control of EID1 turnover will be the focus of Specific aim 2. Preliminary data suggests a role of pRB and RBP2 in differentiation-dependent chromatin remodeling. The functional significance of pRB/RBP2 interactions will be addressed in Specific aim 3 and specific aim 4 will ask whether EID1 and/or RBP2 contribute to the developmental abnormalities observed in RB-/- mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076120-10
Application #
7418297
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Yassin, Rihab R,
Project Start
1998-08-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2010-04-30
Support Year
10
Fiscal Year
2008
Total Cost
$291,851
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Oser, Matthew G; Fonseca, Raquel; Chakraborty, Abhishek A et al. (2018) Cells Lacking the RB1 Tumor Suppressor Gene are Hyperdependent on Aurora B Kinase for Survival. Cancer Discov :
Brier, Ann-Sofie B; Loft, Anne; Madsen, Jesper G S et al. (2017) The KDM5 family is required for activation of pro-proliferative cell cycle genes during adipocyte differentiation. Nucleic Acids Res 45:1743-1759
Zou, Mike Ran; Cao, Jian; Liu, Zongzhi et al. (2014) Histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) controls mammary gland development by regulating key developmental and lineage specification genes. J Biol Chem 289:17620-33
Lu, Gang; Zhang, Qing; Huang, Ying et al. (2014) Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor. Cancer Cell 26:222-34
Lu, Gang; Middleton, Richard E; Sun, Huahang et al. (2014) The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305-9
Kaelin Jr, William G; McKnight, Steven L (2013) Influence of metabolism on epigenetics and disease. Cell 153:56-69
Losman, Julie-Aurore; Kaelin Jr, William G (2013) What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 27:836-52
Beshiri, Michael L; Holmes, Katherine B; Richter, William F et al. (2012) Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation. Proc Natl Acad Sci U S A 109:18499-504
Kaelin Jr, William G (2012) Molecular biology. Use and abuse of RNAi to study mammalian gene function. Science 337:421-2
Kaelin Jr, W G (2011) Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases. Cold Spring Harb Symp Quant Biol 76:335-45

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