Cellular differentiation is tightly coordinated with, and dependent upon, permanent cell cycle exit. The tumor suppressor pRB prevents tumorigenesis by virtue of its ability to suppress proliferation. It is clear that the pRB tumor family, which is comprised of pRB and the related proteins, p107 and p130 (also known as pocket proteins), is recruited to promoters through the E2F transcription factor. Once recruited, pocket proteins coordinate changes in gene expression with cell cycle progression and cell cycle exit, during transient growth arrest (quiescence) and permanent growth arrest that occurs upon cellular differentiation. Pocket proteins play a role in recruiting a cadre of co-repressors, such as Sin3-HDAC and histone methyltransferases, that modify chromatin and silence gene expression. Yet the mechanisms underlying the pRB-dependent changes in gene expression are not well understood. It is important to unravel these mechanisms, since they are likely to shed light on transcriptional controls associated with normal cell growth and tumor suppressive mechanisms. It is also unclear what transcriptional controls distinguish cells progressing through the M/G1 phase transition from those observed in cells re-emerging from growth arrest (the G0/G1 phase transition) and how differences in factor recruitment and chromatin modifications dictate transient growth arrest versus permanent cell cycle exit. We have found that pRB and the Sin3 co-repressor play a role in both settings. In this proposal, we seek to build upon results of the previous funding period and explore answers to these fundamental issues in the following Aims: (1) We will examine the role of E2F, pocket proteins, and Sin3 isoforms in factor recruitment, chromatin modification, and nucleosome remodeling during permanent cell cycle exit in muscle cells. (2) We will determine whether Sin3A and Sin3B isoforms can specifically regulate target gene transcription and purify endogenous complexes. (3) We will investigate the phenotype of Sin3 conditional knock-outs and attempt to unravel a role for Sin3 isoforms in maintaining cell cycle arrest in an animal model.

Public Health Relevance

Cells that fail to exit the cell cycle and differentiate can over-proliferate, promoting tumorigenesis. Loss of the pRB tumor suppressor can lead to de-repression of cell cycle genes and abnormal proliferation, expanding the population of cells that can sustain a second genetic mutation. Permanent cell cycle exit and differentiation are tightly coupled. It is known that the retinoblastoma (pRB) tumor suppressor family plays a pivotal role in controlling growth arrest and differentiation, in part through its association with co-repressors such as Sin3, and its ability to epigenetically modify chromatin. This proposal seeks to understand the underlying chromatin modifications and remodeling mechanisms whereby the pRB family and the Sin3 co-repressor regulate gene expression during cell cycle progression and growth arrest.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077245-15
Application #
8265295
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Mietz, Judy
Project Start
1998-06-19
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
15
Fiscal Year
2012
Total Cost
$337,871
Indirect Cost
$138,480
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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