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Journal of Virology, June 2003, p. 7106-7112, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.7106-7112.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Activated Notch1 Inhibits p53-Induced Apoptosis and Sustains Transformation by Human Papillomavirus Type 16 E6 and E7 Oncogenes through a PI3K-PKB/Akt-Dependent Pathway

Pradip Nair,1* Kumaravel Somasundaram,2 and Sudhir Krishna1

National Centre for Biological Sciences, TIFR, GKVK Campus, Bangalore 560 065,1 Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India2

Received 3 December 2002/ Accepted 18 March 2003

Activated Notch1 (AcN1) alleles cooperate with oncogenes from DNA tumor viruses in transformation of epithelial cells. AcN1 signaling has pleiotropic effects, and suggested oncogenic roles include driving proliferation through cyclin D1 or the generation of resistance to apoptosis on matrix withdrawal through a phosphatidylinositol 3-kinase (PI3K)-PKB/Akt-dependent pathway. Here, we extend the antiapoptotic role for AcN1 by showing inhibition of p53-induced apoptosis and transactivation. Chemical inhibitors of the PI3K pathway block AcN1-induced inhibition of p53-dependent apoptosis and nuclear localization of Hdm2. We show that expression of wild-type p53 does not inhibit synergistic transformation by AcN1 and human papillomavirus E6 and E7 oncogenes. We suggest that activation of Notch signaling may serve as an additional mechanism to inhibit wild-type p53 function in papillomavirus-associated neoplasia.

* Corresponding author. Mailing address: National Centre for Biological Sciences, TIFR, GKVK Campus, Bangalore 560 065, India. Phone: 91-80-3636421, ext. 2271. Fax: 91-80-3636662. E-mail: pradip{at}ncbs.res.in.

Journal of Virology, June 2003, p. 7106-7112, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.7106-7112.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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