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Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation
Abstract
The Notch family of cell surface receptors plays a key role in cell-fate determination and differentiation, functioning in a cell- and context-specific manner. In mammalian cells, Notch activation is generally thought to maintain stem cell potential and inhibit differentiation, thereby promoting carcinogenesis. However, in other contexts such as primary epithelial cells (keratinocytes), increased Notch activity causes exit from the cell cycle and/or commitment to differentiation. We now report that expression of the endogenous Notch1 gene is markedly reduced in a panel of cervical carcinoma cells whereas expression of Notch2 remains elevated, and Notch1 expression is similarly reduced or absent in invasive cervical cancers. Conversely, expression of activated Notch1 causes strong growth inhibition of HPV-positive, but not HPV-negative, cervical carcinoma cells, but exerts no such effects on other epithelial tumor cells. Increased Notch1 signaling, but not Notch2, causes a dramatic down-modulation of HPV-driven transcription of the E6/E7 viral genes, through suppression of AP-1 activity by up-regulation of the Fra-1 family member and decreased c-Fos expression. Thus, Notch1 exerts specific protective effects against HPV-induced transformation through suppression of E6/E7 expression, and down-modulation of Notch1 expression is likely to play an important role in late stages of HPV-induced carcinogenesis.
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“Both EP300 and NOTCH1 are recurrently mutated in diverse cancers and are involved in Notch signaling, a pathway dysregulated in HeLa15.”
From The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line (2013) · cites this paper as [15]
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Cites
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“Thus, E6 targets the p53 tumor suppressor protein for ubiquination and degradation (Scheffner et al. 1990), whereas E7 functionally inactivates p105-Rb (Dyson et al. 1989).”
Background
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Cited by
The Fos family of transcription factors and their role in tumourigenesis
Milde-Langosch, K. (2005) · European Journal of Cancer · doi:10.1016/j.ejca.2005.08.008 · Cited by 583
Narisawa‐Saito, M., & Kiyono, T. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00546.x · Cited by 528
The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line
Adey, A., Burton, J. N., Kitzman, J. O., Hiatt, J. B., Lewis, A. P., Martin, B. K., Qiu, R., Lee, C., & Shendure, J. (2013) · Nature · doi:10.1038/nature12064 · Cited by 362
Role of Notch signaling in colorectal cancer
Qiao, L., & Wong, B. C. Y. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp236 · Cited by 154
Brimer, N., Lyons, C., Wallberg, A. E., & Vande Pol, S. B. (2012) · Oncogene · doi:10.1038/onc.2011.589 · Cited by 133
Metadata
- Authors
- Talora, C., Sgroi, D. C., Crum, C. P., & Dotto, G. P.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2002-09-01
- Volume
- 16
- Issue
- 17
- Pages
- 2252-2263
- ISSN
- 0890-9369
- 1549-5477
- Cited by
- 206
- References
- 1
- Language
- en
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