Pten deficiency in melanocytes results in resistance to hair graying and susceptibility to carcinogen-induced melanomagenesis.
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.
Inoue-Narita
Tae
T
Department of Dermatology, Akita University School of Medicine, Akita, Japan.
Hamada
Koichi
K
Sasaki
Takehiko
T
Hatakeyama
Sachiko
S
Fujita
Sachiko
S
Kawahara
Kohichi
K
Sasaki
Masato
M
Kishimoto
Hiroyuki
H
Eguchi
Satoshi
S
Kojima
Itaru
I
Beermann
Friedrich
F
Kimura
Tetsunori
T
Osawa
Masatake
M
Itami
Satoshi
S
Mak
Tak Wah
TW
Nakano
Toru
T
Manabe
Motomu
M
Suzuki
Akira
A
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006200:Hair Color / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism; D008545:Melanoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology
D002273:Carcinogens; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse