Abstract
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.
Highlights
Melanocytes produce the pigment melanin that governs hair color
Quantitative PCR analysis confirmed that the efficiency of Cre recombination in total cultured primary melanocytes of DctCrePtenflox/flox mice was about 70% to 75% (Supplementary Fig. S1B). [Quantitation was established in preliminary PCR experiments using mixtures of various ratios of PtenD and Ptenflox www.aacrjournals.org
Cancer Research plasmid DNAs under identical PCR conditions (Supplementary Fig. S1C).] Western blotting of cultured primary DctCrePtenflox/flox melanocytes confirmed that Pten protein was proportionately reduced in these cells (Supplementary Fig. S1D), and immunohistochemical analysis showed that 92% to 98% of these melanocytes were Dct+
Summary
Melanocytes produce the pigment melanin that governs hair color. Melanocytes in the hair follicles arise from melanoblasts that originate in the embryonic neural crest. Hair regeneration initiates at the early anagen stage in the bulge area of the follicle, where stem cells that give rise to follicular keratinocytes reside [1]. Within the basal portion of the hair follicles, the hair matrix, composed of keratinocytes and melanocytes, grows downward during anagen. The hair follicles regress and become resting at the telogen stage.
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