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Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCK kinases

¹ Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland; ² Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA; ³ Laboratory of Cancer Pharmacogenomics, Fondo "Edo Tempia," Biella 13900, Italy; ⁴ Department of Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne CH-1011, Switzerland; ⁵ Department of Dermatology, Centre Hospitalier Universitaire Vaudois, Lausanne CH-1011, Switzerland; ⁶ Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; ⁷ Division of Cancer Biology and Tissue Engineering, Tufts University Dental School, Boston, Massachusetts 02111, USA

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 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.

[Keywords: Notch; p53; ROCK/MRCK; stem cells; squamous cell carcinoma; in vivo siRNA delivery]

Received August 22, 2006; revised version accepted January 18, 2007.

E-MAIL Gian-Paolo.Dotto{at}unil.ch; FAX 41-21-692-5705.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1484707

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