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↵1H.W. and Y.W. contributed equally to this work.
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Contributed by Peter G. Schultz, August 19, 2009 (sent for review July 1, 2009)
Abstract
Malignant melanoma is the most aggressive form of cutaneous carcinoma, accounting for 75% of all deaths caused by skin cancers. Microphthalmia-associated transcription factor (MITF) is a master gene regulating melanocyte development and functions as a “lineage addiction” oncogene in malignant melanoma. We have identified the receptor protein tyrosine kinase TYRO3 as an upstream regulator of MITF expression by a genome-wide gain-of-function cDNA screen and show that TYRO3 induces MITF-M expression in a SOX10-dependent manner in melanoma cells. Expression of TYRO3 is significantly elevated in human primary melanoma tissue samples and melanoma cell lines and correlates with MITF-M mRNA levels. TYRO3 overexpression bypasses BRAF(V600E)-induced senescence in primary melanocytes, inducing transformation of non-tumorigenic cell lines. Furthermore, TYRO3 knockdown represses cellular proliferation and colony formation in melanoma cells, and sensitizes them to chemotherapeutic agent-induced apoptosis; TYRO3 knockdown in melanoma cells also inhibits tumorigenesis in vivo. Taken together, these data indicate that TYRO3 may serve as a target for the development of therapeutic agents for melanoma.
Footnotes
- 2To whom correspondence may be addressed. E-mail: schultz{at}scripps.edu or xwu{at}gnf.org
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Author contributions: S.Z., H.W., P.G.S., and X.W. designed research; S.Z., H.W., Y.W., A.G., H.T., J.L., F.Y., and B.P.T. performed research; S.Z., H.W., Y.W., A.G., H.T., C.A.L., L.M., J.W., F.S., A.O., P.G.S., and X.W. analyzed data; and S.Z., H.W., C.A.L., P.G.S., and X.W. wrote the paper.
The authors declare no conflict of interest.
A genomic screen identifies TYRO3 as a MITF regulator in melanoma
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