Abstract

The adenovirus (Ad) E1A oncoprotein can function as a transcriptional activator, a transcriptional repressor, a transforming protein, and some serotypes can function as tumorigenic proteins. These E1A functions are encoded by distinct subdomains of the protein many of which interact with specific cellular proteins including transcription factors. E1A interacts with cellular transcription factors Rb and p300 to deregulate cell growth. The E1A of Ad12 transformed cells represses expression of the major histocompatibility class I (MHCI) genes and this effect may allow virally infected cells to escape immune surveillance. In cells transformed by Ad12 E1A the promoter of the MHC H2K(b) gene shows decreased association with the activator NFkB at an R1 site and increased binding of the repressor COUP-TFII at a R2 site. Elucidation of these E1A effects on NFkB and COUP are the subject of the proposal. Also the ability of E1A to activate transcription will be studied by inhibition of E1A association with the hTAF135 by antibodies or introduced mutations. In addition NMR studies will be used to provide structural information.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA029797-18
Application #
2837591
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Daschner, Phillip J
Project Start
1981-04-01
Project End
2001-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
18
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Guan, Hancheng; Ricciardi, Robert P (2012) Transformation by E1A oncoprotein involves ubiquitin-mediated proteolysis of the neuronal and tumor repressor REST in the nucleus. J Virol 86:5594-602
Heyward, Christa Y; Patel, Rajen; Mace, Emily M et al. (2012) Tumorigenic adenovirus 12 cells evade NK cell lysis by reducing the expression of NKG2D ligands. Immunol Lett 144:16-23
Jiao, Junfang; Guan, Hancheng; Lippa, Andrew M et al. (2010) The N terminus of adenovirus type 12 E1A inhibits major histocompatibility complex class I expression by preventing phosphorylation of NF-kappaB p65 Ser276 through direct binding. J Virol 84:7668-74
Guan, Hancheng; Williams, Jim F; Ricciardi, Robert P (2009) Induction of neuronal and tumor-related genes by adenovirus type 12 E1A. J Virol 83:651-61
Guan, Hancheng; Jiao, Junfang; Ricciardi, Robert P (2008) Tumorigenic adenovirus type 12 E1A inhibits phosphorylation of NF-kappaB by PKAc, causing loss of DNA binding and transactivation. J Virol 82:40-8
Guan, Hancheng; Hou, Shihe; Ricciardi, Robert P (2005) DNA binding of repressor nuclear factor-kappaB p50/p50 depends on phosphorylation of Ser337 by the protein kinase A catalytic subunit. J Biol Chem 280:9957-62
Williams, J F; Zhang, Y; Williams, M A et al. (2004) E1A-based determinants of oncogenicity in human adenovirus groups A and C. Curr Top Microbiol Immunol 273:245-88
Guan, Hancheng; Smirnov, Denis A; Ricciardi, Robert P (2003) Identification of genes associated with adenovirus 12 tumorigenesis by microarray. Virology 309:114-24
Zhao, Biwei; Hou, Shihe; Ricciardi, Robert P (2003) Chromatin repression by COUP-TFII and HDAC dominates activation by NF-kappaB in regulating major histocompatibility complex class I transcription in adenovirus tumorigenic cells. Virology 306:68-76
Hou, Shihe; Guan, Hancheng; Ricciardi, Robert P (2003) Phosphorylation of serine 337 of NF-kappaB p50 is critical for DNA binding. J Biol Chem 278:45994-8

Showing the most recent 10 out of 48 publications