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Journal of Virology, June 2004, p. 5934-5945, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5934-5945.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Human Papillomavirus Type 16 E6 Amino Acid 83 Variants Enhance E6-Mediated MAPK Signaling and Differentially Regulate Tumorigenesis by Notch Signaling and Oncogenic Ras

Oishee Chakrabarti,1* Karthikeyan Veeraraghavalu,1 Vinay Tergaonkar,1 Yun Liu,2 Elliot J. Androphy,2 Margaret A. Stanley,3 and Sudhir Krishna1

National Centre for Biological Sciences, TIFR, Bangalore 560065, India,1 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts,2 Department of Pathology, University of Cambridge, Cambridge, United Kingdom3

Received 16 September 2003/ Accepted 11 February 2004

Oncogenically high-risk human papillomaviruses (HPVs) are causally associated with the progression of major human neoplasia-like cancers of the cervix. Several studies have defined functions of the key E6 and E7 oncoproteins in epithelial cell immortalization. The roles of these oncogenes in the progression of immortalized epithelial cells to invasive tumors are still poorly understood. Here, we establish a novel link between the E6 oncoprotein and activation of mitogen-activated protein kinase (MAPK) signaling and show that this signaling involves Rap1. We find that activated MAPK signaling cooperates with deregulated Notch1 signaling to recreate features of HPV-driven invasive cervical carcinomas. We extend our analysis to evaluate an E6 (amino acid [aa] 83) variant that has been linked to invasive tumors. The variant enhances MAPK signaling and cooperative transformation with deregulated Notch1 signaling. Unlike E6, this variant surprisingly inhibits oncogenic Ras-mediated transformation. Our data reveal that the quantitative differences in activation of MAPK signaling by E6 and its variant correlate with differences in cooperative transformation with other signaling pathways, thus suggesting that thresholds of MAPK activation may define permissive conditions for other signaling pathways in tumorigenesis. Epidemiological studies have suggested the importance of E6 aa 83 variants in invasive carcinomas; our data support a key deterministic role for this variant in human cervical tumorigenesis. These observations, along with our recent data showing that deregulated Notch signaling activates phosphatidylinositol 3-kinase signaling, strengthen the possibility of the existence of Ras-independent mechanisms to recreate signaling through classical Ras effector pathways.

* Corresponding author. Mailing address: National Centre for Biological Sciences, TIFR, UAS-GKVK Campus, Bangalore 560065, India. Phone: 91-80-3636421. Fax: 91-80-3636662. E-mail: oishee{at}ncbs.res.in.

Journal of Virology, June 2004, p. 5934-5945, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5934-5945.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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