The retinoblastoma gene, Rb, is the prototypical tumor suppressor. Inactivation of the Rb gene has been implicated in a variety of human cancers. Rb-deficient mice die in utero, suggesting that the retinoblastoma gene product, pRb, has an critical role in development. A complete understanding of the role of pRb in development and cancer does not exist. The Ras proteins-H-Ras, K-Ras4a, K-Ras4b, and N-Ras-are encoded by the most frequently mutated proto-oncogenes in human cancer. Genetic analysis in the mouse indicate that certain Ras members are important for development. Thus, both pRb and Ras play key roles in development and cancer. The function of these proteins is known to be connected. pRb has been identified as an ultimate downstream target of Ras-mediated mitogenic signaling. In this regard, virtually all studies focused on Ras signaling pertain to the unidirectional flow of information from the cell surface to the nucleus. Recent preliminary data from our laboratory suggests that pRb can in turn regulate Ras activity, suggesting that nuclear-cytoplasmic signaling is bidirectional. The broad objective of the proposed research is to examine how pRb exerts its effect on Ras. An understanding of the bi-directional communication between these two proteins will provide new insights into the role of both pRb and Ras in cancer and development. The work will examine the genetic determinants of pRb-mediated suppression of Ras activity. An effort will be made to identify and characterize the component(s) in the pathway connecting pRb and Ras. The research will explore the biological significance of elevated Ras activity following pRb to both in vitro and in the mouse. Focus here will be placed on defining the contribution of pRb-mediated regulation of Ras to murine development and neoplastic transformation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA065842-07S1
Application #
6446480
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Rosenfeld, Bobby
Project Start
1995-08-10
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
7
Fiscal Year
2001
Total Cost
$69,563
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
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