High-risk human papillomaviruses (HPVs), including HPV16, are present in nearly all cervical carcinomas. However, not all women with high-risk HPVs develop cervical cancer. Although there is evidence for synergism between steroid hormones and HPV in the induction and progression of cervical neoplasia, the molecular mechanism is unknown. Preliminary evidence shows that the HPV16 E7 oncoprotein can interact with a component of steroid hormone signaling, steroid receptor coactivator-1 (SRC-1). This proposal aims to characterize this interaction by mutant mapping, coimmunoprecipitation and reporter assays. Changes in the components and activity of the SRC-1 complex by expression of E7 will be determined using an SRC-1 interaction array and histone modification assays. Lastly, initial studies suggest that E7 re-localizes SRC-1 to the cytoplasm, the mechanism for which will be determined. We propose that HPV16 E7 dysregulates hormone-dependent gene expression through its interaction with SRC-1, and is subsequently the molecular mechanism by which steroid hormones act as a cofactor in the induction of cervical neoplasia. These studies will further the understanding of how viral proteins interact with cellular factors to induce cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA112978-01A1
Application #
6998072
Study Section
Special Emphasis Panel (ZRG1-F09 (20))
Program Officer
Lohrey, Nancy
Project Start
2005-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$48,296
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Baldwin, Amy; Grueneberg, Dorre A; Hellner, Karin et al. (2010) Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3. Proc Natl Acad Sci U S A 107:12463-8
Baldwin, Amy; Li, Wenliang; Grace, Miranda et al. (2008) Kinase requirements in human cells: II. Genetic interaction screens identify kinase requirements following HPV16 E7 expression in cancer cells. Proc Natl Acad Sci U S A 105:16478-83
Baldwin, Amy; Huh, Kyung-Won; Munger, Karl (2006) Human papillomavirus E7 oncoprotein dysregulates steroid receptor coactivator 1 localization and function. J Virol 80:6669-77