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J. Biol. Chem., Vol. 281, Issue 15, 10365-10373, April 14, 2006

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c-Met Expression Is Regulated by Mitf in the Melanocyte Lineage^*

Gaël G. McGill¹, Rizwan Haq, Emi K. Nishimura^¶, and David E. Fisher, A Distinguished Clinical Scholar of the Doris Duke Foundation and the Charles and Jan Nirenberg Fellow in Pediatric Oncology at the Dana-Farber Cancer Institute²

From the Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, Department of Internal Medicine, Johns Hopkins Hospital, Baltimore, Maryland 21205, and ^¶Department of Dermatology and Creative Research Institute Sousei, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku Sapporo 060-8638, Japan

Hepatocyte growth factor (HGF)/c-Met signaling is thought to be a key pathway in both melanocyte development and melanoma metastasis. Here, HGF stimulation of melanocytes was seen to up-regulate c-Met expression. In an effort to decipher the mechanism by which HGF up-regulates its receptor, we found that c-Met is a direct transcriptional target of Mitf. This was confirmed with chromatin immunoprecipitation experiments of the human c-Met promoter, as well as by the ability of adenovirally expressed Mitf to modulate endogenous c-Met protein levels in melanocytes. Disruption of Mitf blocked HGF-dependent increases in endogenous c-Met message and protein levels, indicating that HGF regulates its own receptor levels via Mitf. Finally, dominant-negative inhibition of Mitf resulted in profound resistance of melanocytes and melanoma cells to HGF-dependent matrix invasion, suggesting a physiologic role for this pathway in melanocytic development and melanoma.

Received for publication, December 8, 2005 , and in revised form, February 2, 2006.

^* This work was supported in part by a National Institutes of Health grant (to D. E. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Howard Hughes Medical Institute predoctoral fellowship and a Sandoz fellowship.

² To whom correspondence should be addressed: Dept. of Pediatric Oncology, Dana Farber Cancer Inst., 44 Binney St., Boston, MA 02115. Tel.: 617-632-4916; Fax: 617-632-2085; E-mail: david_fisher{at}dfci.harvard.edu.

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