Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways

Claudio Talora, Samantha Cialfi, Oreste Segatto, Stefania Morrone, John Kim Choi, Luigi Frati, Gian Paolo Dotto, Alberto Gulino, Isabella Screpanti

Research output: Contribution to journalArticlepeer-review


Notch signaling plays a key role in cell-fate determination and differentiation in different organisms and cell types. Several reports suggest that Notch signaling may be involved in neoplastic transformation. However, in primary keratinocytes, Notch1 can function as a tumor suppressor. Similarly, in HPV-positive cervical cancer cells, constitutively active Notch1 signaling was found to cause growth suppression. Activated Notch1 in these cells represses viral E6/E7 expression through AP-1 down-modulation, resulting in increased p53 expression and a block of pRb hyperphosphorylation. Here we show that in cervical cancer cell lines in which Notch1 ability to repress AP-1 activity is impaired, Notch1-enforced expression elicits an alternative pathway leading to growth arrest. Indeed, activated Notch1 signaling suppresses activity of the helix-loop-helix transcription factor E47, via ERK1/2 activation, resulting in inhibition of cell cycle progression. Moreover, we found that RBP-Jκ-dependent Notch signaling is specifically repressed in cervical cancer cells and this repression could provide one such mechanism that needs to be activated for cervical carcinogenesis. Finally, we show that inhibition of endogenous Notch1 signaling, although results in a proliferative advantage, sensitizes cervical cancer cell lines to drug-induced apoptosis. Together, our results provide novel molecular insights into Notch1-dependent growth inhibitory effects, counteracting the transforming potential of HPV.

Original languageEnglish
Pages (from-to)343-354
Number of pages12
JournalExperimental Cell Research
Issue number2
Publication statusPublished - May 1 2005


  • AP1
  • Cervical cancer
  • E47
  • E6
  • Erk1/2
  • HPV
  • Keratinocyte transformation
  • Notch

ASJC Scopus subject areas

  • Cell Biology


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