Cancer of the uterine cervix is intimately associated with an infection by high-risk human papillomavirus (HPV) types such as HPV-16 or HPV-18. In cervical carcinomas, the two viral oncoproteins E6 and E7 are consistently overexpressed and these tumors are frequently genomically unstable and show centrosome abnormalities. Centrosomes are the major microtubule organizing centers in animal and human cells and have been implicated in multipolar mitoses, chromosome missegregation and aneuploidy, the most common form of genomic instability in cancer. Although centrosome anomalies can be detected in virtually all malignant tumors, the underlying molecular mechanisms are largely unknown. We discovered that HPV-16 E7 rapidly uncouples centrosome duplication from the cell division cycle in normal human cells and stimulates multipolar mitoses and aneuploidy. Previous results suggest that HPV-16 E7 disrupts centrosome duplication through inactivation of pRB family members in combination with additional cellular targets. Moreover, this activity of the E7 oncoprotein requires ubiquitin-proteasome-mediated proteolysis. In addition to centrosome aberrations, we found that HPV-16 E7 expression causes DMA damage.
The aims of this application therefore are: 1) To determine the cellular targets through which HPV-16 E7 induces centrosome overduplication and aberrant licensing of maternal centrioles; 2) To investigate how HPV-16 E7 interferes with proteolytic activity at the centrosome in order to promote abnormal centrosome duplication; and 3) To establish a causative role of HPV-16 E7-induced centrosome anomalies in the development aneuploidy and to explore whether DNA damage in HPV-16 E7-expressing cells is a cause or consequence of aberrant centrosome duplication. Since the HPV E7 oncoprotein subverts cellular targets that are frequently altered in genomically unstable non-virus-associated tumors, our research will help to understand the molecular basis of genomic instability in cancer in general.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112598-03
Application #
7233581
Study Section
Virology - B Study Section (VIRB)
Program Officer
Blair, Donald G
Project Start
2005-07-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$222,472
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Li, Ji; Kim, Sehyun; Kobayashi, Tetsuo et al. (2012) Neurl4, a novel daughter centriole protein, prevents formation of ectopic microtubule organizing centres. EMBO Rep 13:547-53
Korzeniewski, Nina; Treat, Benjamin; Duensing, Stefan (2011) The HPV-16 E7 oncoprotein induces centriole multiplication through deregulation of Polo-like kinase 4 expression. Mol Cancer 10:61
Korzeniewski, Nina; Spardy, Nicole; Duensing, Anette et al. (2011) Genomic instability and cancer: lessons learned from human papillomaviruses. Cancer Lett 305:113-22
Park, Jung Wook; Pitot, Henry C; Strati, Katerina et al. (2010) Deficiencies in the Fanconi anemia DNA damage response pathway increase sensitivity to HPV-associated head and neck cancer. Cancer Res 70:9959-68
Korzeniewski, Nina; Wheeler, Sarah; Chatterjee, Payel et al. (2010) A novel role of the aryl hydrocarbon receptor (AhR) in centrosome amplification - implications for chemoprevention. Mol Cancer 9:153
Duensing, Stefan; Darr, Sebastian; Cuevas, Rolando et al. (2010) Tripeptidyl Peptidase II Is Required for c-MYC-Induced Centriole Overduplication and a Novel Therapeutic Target in c-MYC-Associated Neoplasms. Genes Cancer 1:883-92
Korzeniewski, Nina; Cuevas, Rolando; Duensing, Anette et al. (2010) Daughter centriole elongation is controlled by proteolysis. Mol Biol Cell 21:3942-51
Duensing, Stefan; Duensing, Anette (2010) Bortezomib: killing two birds with one stone in gastrointestinal stromal tumors. Oncotarget 1:6-8
Duensing, Anette; Duensing, Stefan (2010) Centrosomes, polyploidy and cancer. Adv Exp Med Biol 676:93-103
Spardy, Nicole; Covella, Kathryn; Cha, Elliot et al. (2009) Human papillomavirus 16 E7 oncoprotein attenuates DNA damage checkpoint control by increasing the proteolytic turnover of claspin. Cancer Res 69:7022-9

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