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Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis

Departments of ¹ Dermatology, ² Molecular Biology, and ³ Microbiology, Akita University School of Medicine, Akita, Japan; ⁴ Division of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; ⁵ Laboratory of Cell Physiology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan; ⁶ Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Féderale de Lausanne (EPFL), Epalinges, Switzerland; ⁷ Sapporo Institute of Dermatopathology, Sapporo, Japan; ⁸ Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; Departments of ⁹ Regenerative Dermatology and ¹⁰ Pathology, Graduate School of Medicine, Osaka University, Suita, Japan; and ¹¹ The Campbell Family Institute for Breast Cancer Research and Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Akira Suzuki, Division of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. Phone: 81-92-642-6838, Fax: 81-92-632-1499; E-mail: suzuki{at}bioreg.kyushu-u.ac.jp.

Key Words: PTEN • melanocytes • hair graying • melanoma

Phosphate and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor gene inactivated in numerous sporadic cancers, including melanomas. To analyze Pten functions in melanocytes, we used the Cre-loxP system to delete Pten specifically in murine pigment-producing cells and generated DctCrePten^flox/flox mice. Half of DctCrePten^flox/flox mice died shortly after birth with enlargements of the cerebral cortex and hippocampus. Melanocytes were increased in the dermis of perinatal DctCrePten^flox/flox mice. When the mutants were subjected to repeated depilations, melanocyte stem cells in the bulge of the hair follicle resisted exhaustion and the mice were protected against hair graying. Although spontaneous melanomas did not form in DctCrePten^flox/flox mice, large nevi and melanomas developed after carcinogen exposure. DctCrePten^flox/flox melanocytes were increased in size and exhibited heightened activation of Akt and extracellular signal–regulated kinases, increased expression of Bcl-2, and decreased expression of p27^Kip1. Our results show that Pten is important for the maintenance of melanocyte stem cells and the suppression of melanomagenesis. [Cancer Res 2008;68(14):5760–8]