Document Detail


Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways.
MedLine Citation:
PMID:  15817159     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Claudio Talora; Samantha Cialfi; Oreste Segatto; Stefania Morrone; John Kim Choi; Luigi Frati; Gian Paolo Dotto; Alberto Gulino; Isabella Screpanti
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Experimental cell research     Volume:  305     ISSN:  0014-4827     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-04-08     Completed Date:  2005-06-16     Revised Date:  2009-11-23    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  343-54     Citation Subset:  IM    
Affiliation:
Department of Experimental Medicine and Pathology, Laboratory of Molecular Pathology, University La Sapienza, Viale Regina Elena, 324, 00161 Rome, Italy.
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MeSH Terms
Descriptor/Qualifier:
Cell Line, Tumor
Cell Proliferation / drug effects
DNA-Binding Proteins / genetics,  metabolism
Female
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Nuclear Proteins / genetics,  metabolism
Oncogene Proteins, Viral / genetics,  metabolism
Papillomaviridae / isolation & purification,  physiology*
Receptor, Notch1
Receptors, Cell Surface / genetics,  physiology*
Signal Transduction*
TCF Transcription Factors
Tamoxifen / pharmacology
Transcription Factor AP-1 / metabolism
Transcription Factors / genetics,  metabolism,  physiology*
Uterine Cervical Neoplasms / metabolism*,  virology*
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Immunoglobulin J Recombination Signal Sequence-Binding Protein; 0/NOTCH1 protein, human; 0/Nuclear Proteins; 0/Oncogene Proteins, Viral; 0/RBPJ protein, human; 0/Receptor, Notch1; 0/Receptors, Cell Surface; 0/TCF Transcription Factors; 0/Transcription Factor AP-1; 0/Transcription Factors; 0/transcription factor 7-like 1 protein; 10540-29-1/Tamoxifen; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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