The retinoblastoma tumor suppressor, RB, is inactivated in-the majority of human cancers, resulting in growth advantage. While the underlying basis of inactivation encompasses a variety of mechanisms (e.g. deregulated phosphorylation, direct oncoprotein binding, point mutation) all of these result in the disruption of RB assembled complexes. When active, RB is hypophosphorylated and assembles transcriptional repressor complexes to facilitate repression of critical cell cycle genes. Mitogenic signaling cascades or oncogenic lesions stimulate the phosphorylation of RB, thereby disrupting the transcriptional repressor complexes and enabling cell cycle progression. In contrast, anti-mitogenic signals (e.g. DNA-damage) will prevent phosphorylation and maintain RB-repressor complexes to inhibit cellular proliferation. Therefore, understanding RB-mediated transcriptional repression is germane both to regulated cell cycle progression (i.e. the interplay of mitogenic and anti-mitogenic signaling) and tumorigenesis. RB mediates transcriptional repression by recruiting co-repressors to target promoters. These co-repressors have specific affects on chrornatin leading to direct modification of histories (e.g. methylation or deacetylation). Since transcriptional repression is critical for RB function, loss of co-repressors could represent a means through which RB is functionally inactivated in cancer. Of the RB associated co-repressors, SWI/SNF proteins have been implicated as a tumor suppressor through a combination of genetic studies in cell lines, mouse models and expression analysis in primary human tumors. Consistent with the idea that loss of this co-repressor complexes compromise RB signaling, we have found that loss of the core SWI/SNF ATPases (BRG1 and BRM) bypass RB-mediated transcriptional repression and cell cycle inhibition. Therefore, we will test the hypothesis that BRG1/BRM plays a specific role in mediating RB-dependent transcriptional repression to suppress uncontrolled proliferation and tumorigenesis. Specifically, we will (I) determine the mechanism through which BRG1/BRM facilitate the action of RB in transcriptional repression, (11) define the targets of specific RB co-repressor complexes, and (111)specifically elucidate the role of BRG1/BRM and transcriptional repression in RB-dependent tumor suppression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104213-02
Application #
6851688
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mietz, Judy
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2005-06-06
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$251,740
Indirect Cost
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Kuwahara, Yasumichi; Charboneau, Aubri; Knudsen, Erik S et al. (2010) Reexpression of hSNF5 in malignant rhabdoid tumor cell lines causes cell cycle arrest through a p21(CIP1/WAF1)-dependent mechanism. Cancer Res 70:1854-65
Millar, E K A; Dean, J L; McNeil, C M et al. (2009) Cyclin D1b protein expression in breast cancer is independent of cyclin D1a and associated with poor disease outcome. Oncogene 28:1812-20
Bourgo, Ryan J; Braden, Wesley A; Wells, Susanne I et al. (2009) Activation of the retinoblastoma tumor suppressor mediates cell cycle inhibition and cell death in specific cervical cancer cell lines. Mol Carcinog 48:45-55
Bourgo, Ryan J; Siddiqui, Hasan; Fox, Sejal et al. (2009) SWI/SNF deficiency results in aberrant chromatin organization, mitotic failure, and diminished proliferative capacity. Mol Biol Cell 20:3192-9
Hoskins, E E; Gunawardena, R W; Habash, K B et al. (2008) Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway. Oncogene 27:4798-808
Knudsen, Erik S; Knudsen, Karen E (2008) Tailoring to RB: tumour suppressor status and therapeutic response. Nat Rev Cancer 8:714-24
Wang, Ying; Dean, Jeffry L; Millar, Ewan K A et al. (2008) Cyclin D1b is aberrantly regulated in response to therapeutic challenge and promotes resistance to estrogen antagonists. Cancer Res 68:5628-38
Siddiqui, Hasan; Fox, Sejal R; Gunawardena, Ranjaka W et al. (2007) Loss of RB compromises specific heterochromatin modifications and modulates HP1alpha dynamics. J Cell Physiol 211:131-7
Gunawardena, Ranjaka W; Fox, Sejal R; Siddiqui, Hasan et al. (2007) SWI/SNF activity is required for the repression of deoxyribonucleotide triphosphate metabolic enzymes via the recruitment of mSin3B. J Biol Chem 282:20116-23
Seeley, Sarah L; Bosco, Emily E; Kramer, Elizabeth et al. (2007) Distinct roles for RB loss on cell cycle control, cisplatin response, and immortalization in Schwann cells. Cancer Lett 245:205-17

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