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[Cancer Research 63, 674-681, February 1, 2003]
© 2003 American Association for Cancer Research

Molecular Biology and Genetics

Keratinocyte-specific Pten Deficiency Results in Epidermal Hyperplasia, Accelerated Hair Follicle Morphogenesis and Tumor Formation1

Akira Suzuki, Satoshi Itami2, Minako Ohishi2, Koichi Hamada, Tae Inoue, Nobuyasu Komazawa, Haruki Senoo, Takehiko Sasaki, Junji Takeda, Motomu Manabe, Tak Wah Mak3, 4 and Toru Nakano3, 5

Departments of Biochemistry [A. S., K. H.], Dermatology [T. I., M. M.], and Anatomy [H. S.], Akita University School of Medicine, Akita 010-8543, Japan; Department of Molecular Cell Biology, Research Institute for Microbial Disease [M. O., T. N.], Department of Dermatology [S. I.], and Department of Social and Environmental Medicine [N. K., J. T.], Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan [T. S.]; and Advanced Medical Discovery Institute, University of Toronto, Toronto, Ontario, M5G 2C1 Canada [T. W. M.]

PTEN is a tumor suppressor gene mutated in many human cancers. We used the Cre-loxP system to generate a keratinocyte-specific null mutation of Pten in mice (k5Ptenflox/flox mice). k5Ptenflox/flox mice exhibit wrinkled skin because of epidermal hyperplasia and hyperkeratosis and ruffled, shaggy, and curly hair. Histological examination revealed that skin morphogenesis is accelerated in k5Ptenflox/flox mice. Within 3 weeks of birth, 90% of k5Ptenflox/flox mice die of malnutrition possibly caused by hyperkeratosis of the esophagus. All k5Ptenflox/flox mice develop spontaneous tumors within 8.5 months of birth, and chemical treatment accelerates the onset of tumors. k5Ptenflox/flox keratinocytes are hyperproliferative and resistant to apoptosis and show increased activation of the Pten downstream signaling mediators Akt/protein kinase B (PKB) and extracellular signal-regulated kinase. Pten is thus an important regulator of normal development and oncogenesis in the skin.




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