Activating transcription factor-2 (ATF-2) is a member of the CREB (cyclic AMP response element binding protein)/ATF family of transcription factors. Though it is present ubiquitously in mammalian tissues, the role of ATF-2 in normal cellular function is not known. Experiments suggest that ATF-2 has a cell cycle-related role: a) ATF-2 is translocated to the nucleus in Gl and G2/M phase cells, and b) similar nuclear translocation of ATF-2 is seen in response to stimulation with mitogenic growth factors, including epidermal growth factor. Though it has been shown to mediate - transcriptional activation by adenoviral E1a protein, an endogenous cellular regulator of ATF-2 function has not been identified. Adenoviral Ela protein does not directly bind DNA; it is able to activate gene transcription by interacting with DNA-bound ATF-2. We postulate that ATF- 2 interacts with endogenous cellular proteins in a similar fashion to form transcriptional complexes which regulate cell cycle-dependent gene expression. The goal of the experiments described in this proposal is the identification of mammalian proteins that interact with ATF-2 to form transcriptional complexes which transduce positive or negative signals to RNA-polymerase to effect expression of specific genes. This will be accomplished by screening for proteins, expressed by a mouse embryo cDNA library, which interact with ATF-2 in the yeast two-hybrid system. Proteins which interact with ATF-2 will be expressed, purified and sequenced. The tissue specificities, DNA-binding capabilities and transcriptional activation potential of these proteins will be characterized. The CREB/ATF family of transcription factors function in cellular signal transduction and in the regulation of cell growth and differentiation. Experiments based on the structure/function characteristics of CREB and ATF-2 will have implications for guiding future protocols of cancer therapy. Delineation of the role of protein- protein interactions in transcriptional activation is important for understanding the mechanisms involved in the normal and abnormal regulation of gene expression, cell growth, cell differentiation and oncogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Physician Scientist Award (K11)
Project #
5K11CA064401-05
Application #
2748767
Study Section
Cancer Institutional Fellowship Review Committee (CT)
Program Officer
Vargosko, Andrew J
Project Start
1994-08-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
2000-07-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Dunkelberg, J C; Gutierrez-Hartmann, A (2001) LZ-FYVE: a novel developmental stage-specific leucine zipper, FYVE-finger protein. DNA Cell Biol 20:403-12