Vitamin A and its derivatives (retinoids) control numerous, fundamental biological processes, many with relevance to human disease prevention. Notable among these is the ability of retinoids to inhibit the progression of early neoplastic lesions. The mechanism(s) by which retinoids limit oncogenesis are not clear. Retinoid effects on tumor cells involves transcriptional regulation of cellular genes by the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The products of these genes control proliferation, differentiation and apoptosis. Relatively little progress has been made at identifying critical target genes that mediate the anti-oncogenic response to retinoids. The limited pace of these studies results in large part from the lack of an appropriate system in which to assess whether isolated genes are involved in the biological processes under study. We have developed an experimental system that allows us to study the specific effects of ligand activated RARalpha during oncogenic transformation. We used this system to demonstrate that retinoic acid inhibits signaling via a pathway that leads from plasma membrane tyrosine kinases (both receptor and non-receptor), through phosphatidylinositol 3-kinase and Jun N-terminal kinase, to the c-fos promoter. In this application, I am proposing to identify the retinoic acid induced genes that regulate signaling throughout this pathway, identify the specific step(s) in the pathway affected by these retinoid regulated gene products, and determine if regulation of these targets by retinoic acid also controls apoptosis in tumor cells.
The specific aims of the project are: 1. Generation of a population of cDNA probes enriched in RA-induced sequences. 2. Identify the site of RA action in the signaling pathway that links mT activated Ptdlns 3-kinase with the c-fos promoter. 3. Identify the RA target that inhibits apoptosis in mT-transformed cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA079737-01
Application #
2729457
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Mohla, Suresh
Project Start
1999-01-01
Project End
2003-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Nutrition
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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