We propose to continue our studies on the molecular genetic analysis of two early gene regions of human adenovirus 2 (Ad 2). Our studies will focus on the transforming early region E1a and early gene block Ll and will have three major goals. Firstly, using various mutants, we will identify the functional regions essential for E1a mediated immortalization and transformation of epithelial cells and determine their relationship to induction of cellular DNA synthesis and regulation of the cell division cycle. We will attempt to separate the immortalization and transformation functions controlled by one of the E1a T antigens (243R) and elucidate the possiblemechanisms of immortalization and transformation. Our recent studies have revealed that a domain of the 289R protein suppresses immortalization of primary baby rat kidney cells. The second aspect of our study would be to gain insight into the possible mechanisms of immortalization suppression. We propose to identify the cellular genes differentially regulated by the 289R T antigen or the cellular protein factors that may specifically interact with this protein. If exploratory studies indicate that the 289R protein may be a metalloprotein, the effect of the immortalization up mutations on potential metal binding will be investigated. The third major goal of our study would be to elucidate the functions of the 52- 55kD proteins coded by the L1 region in regulation of viral early, intermediate late and true late gene expression using suppressible nonsense mutants or partially defective deletion and/or insertion mutants.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031719-09
Application #
3169800
Study Section
Experimental Virology Study Section (EVR)
Project Start
1982-03-01
Project End
1993-02-28
Budget Start
1990-03-01
Budget End
1991-02-28
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Theodorakis, P; D'Sa-Eipper, C; Subramanian, T et al. (1996) Unmasking of a proliferation-restraining activity of the anti-apoptosis protein EBV BHRF1. Oncogene 12:1707-13
Sollerbrant, K; Chinnadurai, G; Svensson, C (1996) The CtBP binding domain in the adenovirus E1A protein controls CR1-dependent transactivation. Nucleic Acids Res 24:2578-84
D'Sa-Eipper, C; Subramanian, T; Chinnadurai, G (1996) bfl-1, a bcl-2 homologue, suppresses p53-induced apoptosis and exhibits potent cooperative transforming activity. Cancer Res 56:3879-82
Boyd, J M; Gallo, G J; Elangovan, B et al. (1995) Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene 11:1921-8
Subramanian, T; Boyd, J M; Chinnadurai, G (1995) Functional substitution identifies a cell survival promoting domain common to adenovirus E1B 19 kDa and Bcl-2 proteins. Oncogene 11:2403-9
Subramanian, T; Tarodi, B; Chinnadurai, G (1995) p53-independent apoptotic and necrotic cell deaths induced by adenovirus infection: suppression by E1B 19K and Bcl-2 proteins. Cell Growth Differ 6:131-7
Subramanian, T; Tarodi, B; Chinnadurai, G (1995) Functional similarity between adenovirus E1B 19-kDa protein and proteins encoded by Bcl-2 proto-oncogene and Epstein-Barr virus BHRF1 gene. Curr Top Microbiol Immunol 199 ( Pt 1):153-61
Schaeper, U; Boyd, J M; Verma, S et al. (1995) Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation. Proc Natl Acad Sci U S A 92:10467-71
Boyd, J M; Malstrom, S; Subramanian, T et al. (1994) Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell 79:341-51
Tarodi, B; Subramanian, T; Chinnadurai, G (1994) Epstein-Barr virus BHRF1 protein protects against cell death induced by DNA-damaging agents and heterologous viral infection. Virology 201:404-7

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