The long-term goal of this research grant is to define the biochemical basis for the biological activities of the E7 oncoproteins of human papillomaviruses (HPVs). The HPV E7 oncoprotein is one of only two viral gene products that are consistently expressed in HPV-associated cervical cancers. One function of the HPV E7 is the ability to induce cellular DNA synthesis in differentiating human keratinocytes that have normally withdrawn from the cell division cycle. The ability of E7 to uncouple cellular differentiation and proliferation is paramount to ensure replication of viral genomes in differentiating keratinocytes. The principal investigator discovered two activities that contribute to the ability of E7 to maintain differentiating cells in a replication-competent state: the capacity to interact with and inactivate the cyclin dependent kinase inhibitor p21cip1, and the ability to destabilize the retinoblastoma protein pRB. The inhibitor p21cip1 plays an important role in coupling cellular proliferation and differentiation and in E7 expressing keratinocytes cdk2 remains active. The ability of HPV E7 to destabilize pRB correlates with cellular transformation. Transformation deficient mutants of E7 were found to be inactive for pRB destabilization. Possibly as a cellular response to pRB inactivation, E7-expression also causes p53 stabilization. Although p21cip1, a transcriptional target of p53, is also increased in E7 expressing cells, the higher levels are mostly due to protein stabilization. Another consequence of E7 expression in normal cells is the induction of genomic instability. The PI found that E7 can induce aberrant centrosome duplication that leads to abnormal mitotic spindle pole formation and chromosome miss-segregation. They will investigate the biological consequences of pRB destabilization, the biochemical mechanism of E7-mediated pRB destabilization, and whether stabilized p53 is transcriptionally active and whether p21cip1stabilization is a consequence of E7's interaction with p21cip1 containing cellular complexes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA066980-07
Application #
6512871
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1996-04-19
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
7
Fiscal Year
2002
Total Cost
$309,600
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
McBride, Alison A; Münger, Karl (2018) Expert Views on HPV Infection. Viruses 10:
Liu, Zhiyi; Pouli, Dimitra; Alonzo, Carlo A et al. (2018) Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast. Sci Adv 4:eaap9302
Chiang, Cindy; Pauli, Eva-Katharina; Biryukov, Jennifer et al. (2018) The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG-I-Mediated Innate Immune Signaling. J Virol 92:
Gaglia, Marta M; Munger, Karl (2018) More than just oncogenes: mechanisms of tumorigenesis by human viruses. Curr Opin Virol 32:48-59
Meyers, Jordan M; Grace, Miranda; Uberoi, Aayushi et al. (2018) Inhibition of TGF-? and NOTCH Signaling by Cutaneous Papillomaviruses. Front Microbiol 9:389
Sharma, Surendra; Munger, Karl (2018) Expression of the cervical carcinoma expressed PCNA regulatory (CCEPR) long noncoding RNA is driven by the human papillomavirus E6 protein and modulates cell proliferation independent of PCNA. Virology 518:8-13
Wallace, Nicholas A; Münger, Karl (2018) The curious case of APOBEC3 activation by cancer-associated human papillomaviruses. PLoS Pathog 14:e1006717
Miller, Anna K; Munger, Karl; Adler, Frederick R (2017) A Mathematical Model of Cell Cycle Dysregulation Due to Human Papillomavirus Infection. Bull Math Biol 79:1564-1585
Harden, Mallory E; Prasad, Nripesh; Griffiths, Anthony et al. (2017) Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins. MBio 8:
Grace, Miranda; Munger, Karl (2017) Proteomic analysis of the gamma human papillomavirus type 197 E6 and E7 associated cellular proteins. Virology 500:71-81

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