A genomic screen identifies TYRO3 as a MITF regulator in melanoma

作者：Zhu, Shoutian; Wurdak, Heiko; Wang, Yan; Galkin, Anna; Tao, Haiyan; Li, Jie; Lyssiotis, Costas A.; Yan, Feng; Tu, Buu P.; Miraglia, Loren; Walker, John; Sun, Fanxiang; Orth, Anthony; Schultz, Peter G.^*; Wu, Xu

来源：Proceedings of the National Academy of Sciences, 2009, 106(40): 17025-17030.

DOI：10.1073/pnas.0909292106

• RECEPTOR TYROSINE KINASE
• MICROPHTHALMIA TRANSCRIPTION FACTOR
• PROTEIN-S
• GROWTH ARREST
• MALIGNANT-MELANOMA
• LINEAGE SURVIVAL
• BREAST-CANCER
• NEURAL CREST
• CELL-GROWTH
• FACTOR GENE

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.

• 出版日期2009-10-6