Analysis of the mechanisms and components underlying the coupled cellular processes of signal transduction, transcriptional response and cell growth is the major career interest of the applicant for this research grant. Of particular interest is the mechanism by which oncogene proteins regulate these processes. The activated oncogene is essentially a mutant gene, that provides a phenotype revealing continually new aspects of the behavior, design and interactions of regulatory molecules. In this framework, the proposed research promises to yield new insights concerning the interaction of the E1A oncogene with two dissimilarly regulated genes, interstitial collagenase (CL) and type IV collagenase (T4). The proteolytic enzymes encoded by these genes play an important role in tumor metastasis. E1A protein will be used as a critical probe to analyze their regulation. Specifically, an enhancer element of the CL gene promoter, the TPA- Regulatory Element, was found by this investigator to be an E1A-regulated enhancer: E1A represses its activity in one cell line, but activates it in another. The identification of factors that respond to E1A positively or negatively will be achieved by functionally assaying proteins from one cell system in the background of the other. Assays for this purpose will be of two general types, in vitro (e.g., in vitro transcription) and in vivo (transfection or microinjection.) The T4 gene regulatory region will be analyzed further, as both enhancer and silencer elements have been found. One E1A-repressible enhancer element that binds an AP2-like transcription factor will be characterized in more detail, and the mechanism of E1A repression will be analyzed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29GM044573-03
Application #
3468150
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Frisch, S M (1994) E1a induces the expression of epithelial characteristics. J Cell Biol 127:1085-96
Frisch, S M; Francis, H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124:619-26
Frisch, S M (1991) Antioncogenic effect of adenovirus E1A in human tumor cells. Proc Natl Acad Sci U S A 88:9077-81
Frisch, S M; Morisaki, J H (1990) Positive and negative transcriptional elements of the human type IV collagenase gene. Mol Cell Biol 10:6524-32