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.
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.
Nair
Pradip
P
National Centre for Biological Sciences, TIFR, GKVK Campus, Bangalore 560 065, India. pradip@ncbs.res.in
Somasundaram
Kumaravel
K
Krishna
Sudhir
S
D064413:3-Phosphoinositide-Dependent Protein Kinases; D017209:Apoptosis; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism* / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D027383:Papillomaviridae / Q000502:physiology; D050725:Papillomavirus E7 Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D015398:Signal Transduction; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D064413:3-Phosphoinositide-Dependent Protein Kinases; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C068651:E6 protein, Human papillomavirus type 16; C497761:NOTCH1 protein, human; C059731:oncogene protein E7, Human papillomavirus type 16; C494918:AKT1 protein, human