Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways
- Department of Experimental Medicine and Pathology, Laboratory of Molecular Pathology, University 'La Sapienza', Viale Regina Elena, 324, 00161 Rome (Italy)
- Regina Elena Cancer Institute, Via Delle Messi d'Oro, 156, Rome 00158 (Italy)
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104 (United States)
- Institute of Biochemistry University of Lausanne Chemin de Bovaresses 155 CH-1066 Epalinges (Switzerland)
- Department of Experimental Medicine and Pathology, Laboratory of Molecular Pathology, University 'La Sapienza', Viale Regina Elena, 324, 00161 Rome (Italy) and Istituto Pasteur-Fondazione Cenci Bolognetti, University 'La Sapienza', 00161 Roma (Italy)
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-J{kappa}-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.
- OSTI ID:
- 20717591
- Journal Information:
- Experimental Cell Research, Vol. 305, Issue 2; Other Information: DOI: 10.1016/j.yexcr.2005.01.015; PII: S0014-4827(05)00042-X; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
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