Journal
GENES & DEVELOPMENT
Volume 21, Issue 5, Pages 562-577Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1484707
Keywords
notch; p53; ROCK/MRCK; stem cells; squamous cell carcinoma; in vivo siRNA delivery
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Funding
- NCI NIH HHS [CA73796, CA16038, P01 CA016038, R01 CA073796] Funding Source: Medline
- NIAMS NIH HHS [R01 AR039190, AR39190] Funding Source: Medline
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Little is known about the regulation and function of the Notch1 gene in negative control of human tumors. Here we show that Notch1 gene expression and activity are substantially down-modulated in keratinocyte cancer cell lines and tumors, with expression of this gene being under p53 control in these cells. Genetic suppression of Notch signaling in primary human keratinocytes is sufficient, together with activated ras, to cause aggressive squamous cell carcinoma formation. Similar tumor- promoting effects are also caused by in vivo treatment of mice, grafted with keratinocytes expressing oncogenic ras alone, with a pharmacological inhibitor of endogenous Notch signaling. These effects are linked with a lesser commitment of keratinocytes to differentiation, an expansion of stem cell populations, and a mechanism involving up-regulation of ROCK1/2 and MRCK alpha kinases, two key effectors of small Rho GTPases previously implicated in neoplastic progression. Thus, the Notch1 gene is a p53 target with a role in human tumor suppression through negative regulation of Rho effectors.
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