DF/HCC Program Affiliation

Cancer Cell Biology
Gynecologic Cancer

DF/HCC Associations

Associate Director, Program Development, Executive Committee
Member, Center Scientific Council
Institutional Representative for HMS, Executive Committee
Director, Rodent HistoPathology

Research Abstract

The Howley laboratory studies the molecular biology of the papillomaviruses using the bovine papillomavirus (BPV) as well as the human papillomaviruses (HPVs). BPV is the most extensively studied of the papillomaviruses and has served as the model system for the analysis of viral transcription and of viral DNA replication. One focus of our studies has involved the viral E1 and E2 proteins and their roles in the regulation of viral transcription and DNA replication. We are conducting structure/function studies of the viral E1 and E2 proteins with the hope of developing inhibitors of their functions.

There are over 70 different HPVs, and some of them are associated with specific human cancers most notably human cervical cancer. We study the role of these HPVs in human neoplasia and the mechanisms by which these viruses contribute to cellular transformation. The virus encodes two proteins, E6 and E7, that have oncogenic properties and that contribute directly to HPV associated carcinogenesis. A particular focus of the laboratory is the study of the E6 gene, which has multiple functions, including the ability to functionally inactivate p53 by targeting its ubiquitination and proteolysis. This process is mediated by a cellular protein, E6AP, that binds to E6 and functions as a ubiquitin protein ligase in promoting the E6 dependent ubiquitination of p53. We are conducting structure/function studies on E6 and E6AP, and are studying additional functions of the papillomavirus E6 proteins. We have discovered that the BPV E6 protein binds to the cellular focal adhesion protein paxillin leading to a disruption of the actin cytoskeleton. We have also found that HPV16 E6 can bind IRF3 and inhibit its transcriptional activation function.

Publications

• DeMasi J, Huh KW, Nakatani Y, Münger K, Howley PM.Bovine papillomavirus E7 transformation function correlates with cellular p600 protein binding.Proc Natl Acad Sci U S A 2005 Aug 9;102(32):11486-91.
  16081543
• You J, Croyle JL, Nishimura A, Ozato K, Howley PM.Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.Cell 2004 Apr 30;117(3):349-60.
  15109495
• Wells SI, Aronow BJ, Wise TM, Williams SS, Couget JA, Howley PM.Transcriptome signature of irreversible senescence in human papillomavirus-positive cervical cancer cells.Proc Natl Acad Sci U S A 2003 Jun 10;100(12):7093-8.
  12756294
• Wells SI, Francis DA, Karpova AY, Dowhanick JJ, Benson JD, Howley PM.Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21(CIP)-dependent pathways.EMBO J 2000 Nov 1;19(21):5762-71.
  11060027