Human papillomaviruses (HPVs) of the high-risk types induce hyperproliferative lesions in epithelial tissues and are etiologic agents for cancers of the genital cervix and oral cavity. The E6 and E7 oncoproteins encoded by the high-risk HPVs are believed to play central roles in the development of the HPV-related malignancies. The goal of this proposal is to elucidate the mechanisms by which the E7 oncoprotein modifies functions of the host cell regulators. The proposal stems from the observation that E7 specifically induces the proteolytic degradation of the tumor suppressor Rb. Moreover, inhibitors of 26S proteasome inhibit E7- induced degradation of Rb. A main objective of the proposal is to determine the basis of the specificity and analyze the mechanism by which E7 causes proteolysis of Rb. By regulating Rb, E7 increases the transcriptional activity of the E2F-family of transcription factors (E2Fs). Interestingly, E7 also increases the activity of the DNA repair protein DDB that functions as a transcriptional coactivator of E2Fs. DDB possesses homology with the Cockayne syndrome protein GS-A, which is involved in transcription-coupled repair (TCR). The proposal focuses on the role of the E7 mediated increase in DDB in the activation of E2Fs as well as in DNA repair. The hypothesis that E7, by increasing the activity of DDB, stimulates TCR of the E2F-regulated replication genes will be investigated. These studies on the repair function of E7 will provide insights into the mechanisms of drug resistance in cervical cancer patients.
The specific aims are: 1. What is the basis of specificity of Rb-degradation by E7? 2. What is the mechanism by which E7 causes proteolysis of Rb? 3. Does E7 play a role in transcription-coupled repair of the E2F- regulated replication genes?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA076276-01A2
Application #
2843988
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Wong, May
Project Start
1999-05-20
Project End
2003-04-30
Budget Start
1999-05-20
Budget End
2000-04-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Pan, Wei; Datta, Abhishek; Adami, Guy R et al. (2003) P19ARF inhibits the functions of the HPV16 E7 oncoprotein. Oncogene 22:5496-503
Wang, J; Sampath, A; Raychaudhuri, P et al. (2001) Both Rb and E7 are regulated by the ubiquitin proteasome pathway in HPV-containing cervical tumor cells. Oncogene 20:4740-9
Nag, A; Datta, A; Yoo, K et al. (2001) DDB2 induces nuclear accumulation of the hepatitis B virus X protein independently of binding to DDB1. J Virol 75:10383-92
Shiyanov, P; Nag, A; Raychaudhuri, P (1999) Cullin 4A associates with the UV-damaged DNA-binding protein DDB. J Biol Chem 274:35309-12