title: Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways.
abstract: 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-Jkappa-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.
authors.affiliation: Department of Experimental Medicine and Pathology, Laboratory of Molecular Pathology, University La Sapienza, Viale Regina Elena, 324, 00161 Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Talora
authors.forename: Samantha
authors.initials: S
authors.lastname: Cialfi
authors.forename: Oreste
authors.initials: O
authors.lastname: Segatto
authors.forename: Stefania
authors.initials: S
authors.lastname: Morrone
authors.forename: John
authors.initials: J
authors.lastname: Kim Choi
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Gian
authors.initials: G
authors.lastname: Paolo Dotto
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D027383:Papillomaviridae / Q000302:isolation & purification / Q000502:physiology*; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051820:TCF Transcription Factors; D013629:Tamoxifen / Q000494:pharmacology; D058125:Transcription Factor 7-Like 1 Protein; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000821:virology*
chemical_list: D004268:DNA-Binding Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497761:NOTCH1 protein, human; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; C497570:RBPJ protein, human; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; D058125:Transcription Factor 7-Like 1 Protein; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D013629:Tamoxifen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3