Abstract

Adenovirus encodes two genes involved in transformation, E1A and E1B, which cooperate to transform primary rodent cells.The E1A gene products stimulate cell proliferation but fail to transform cells alone due to the induction of programmed cell death (apoptosis). Expression of the E1B gene or the human bcl-2 proto-oncogene, blocks E1A-induced cell death to produce transformation with high efficiency. The E1B gene encodes two products the l9K and 55K proteins that are unique proteins. Both of these proteins enhance transformation by E1A by blocking induced cell death. Additionally, the E1B 19K protein can block apoptosis induced by tumor necrosis factor-a (TNF-a) and anti-Fas antibodies. Recent results from Dr. White's laboratory has shown that the E1A proteins induce p53 which in turn induces apoptosis. The E1B 55K protein directly binds p53 and presumably interferes with it's function like SV40 T antigen. The mechanism of action of the E1B l9K protein in suppression of p53 is unknown.
The aim of this proposal is to ascertain the mechanism by which apoptosis by p53 is regulated. The approach is to define how E1A, c-myc, TNF-a, and anti-Fas antibodies induce p53 and apoptosis and how the E1B l9K and bcl-2 proteins block this effect.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA060088-02
Application #
2100712
Study Section
Virology Study Section (VR)
Project Start
1994-03-01
Project End
1997-02-28
Budget Start
1995-03-01
Budget End
1996-02-29
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
Rutgers University
Department
Type
Organized Research Units
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901

  Publications

Kimmelman, Alec C; White, Eileen (2017) Autophagy and Tumor Metabolism. Cell Metab 25:1037-1043
Guo, Jessie Yanxiang; White, Eileen (2013) Autophagy is required for mitochondrial function, lipid metabolism, growth, and fate of KRAS(G12D)-driven lung tumors. Autophagy 9:1636-8
Henry, Holly; Thomas, Anju; Shen, Yan et al. (2002) Regulation of the mitochondrial checkpoint in p53-mediated apoptosis confers resistance to cell death. Oncogene 21:748-60
Sullivan, Gregory F; Garcia-Welch, Adrienne; White, Eileen et al. (2002) Augmentation of apoptosis by the combination of bleomycin with trifluoperazine in the presence of mutant p53. J Exp Ther Oncol 2:19-26
Degenhardt, Kurt; Chen, Guanghua; Lindsten, Tullia et al. (2002) BAX and BAK mediate p53-independent suppression of tumorigenesis. Cancer Cell 2:193-203
Cuconati, Andrea; White, Eileen (2002) Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection. Genes Dev 16:2465-78
Thomas, A; Giesler, T; White, E (2000) p53 mediates bcl-2 phosphorylation and apoptosis via activation of the Cdc42/JNK1 pathway. Oncogene 19:5259-69
Chiou, S K; White, E (1998) Inhibition of ICE-like proteases inhibits apoptosis and increases virus production during adenovirus infection. Virology 244:108-18
Thomas, A; White, E (1998) Suppression of the p300-dependent mdm2 negative-feedback loop induces the p53 apoptotic function. Genes Dev 12:1975-85
Sakamuro, D; Sabbatini, P; White, E et al. (1997) The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 15:887-98

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