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Oncogene. 2015 Aug 27;34(35):4647-55. doi: 10.1038/onc.2014.398. Epub 2014 Dec 8.

Abrogation of protein phosphatase 6 promotes skin carcinogenesis induced by DMBA.

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Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan.
Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Nara, Japan.
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Japan.
Division of Pathology, Miyagi Cancer Center, Miyagi, Japan.
Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.


Somatic mutations in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) have been identified in malignant melanoma and are thought to function as a driver in B-raf- or N-ras-driven tumorigenesis. To assess the role of Ppp6c in carcinogenesis, we generated skin keratinocyte-specific Ppp6c conditional knockout mice and performed two-stage skin carcinogenesis analysis. Ppp6c deficiency induced papilloma formation with 7,12-dimethylbenz (a) anthracene (DMBA) only, and development of those papillomas was significantly accelerated compared with that seen following DMBA/TPA (12-O-tetradecanoylphorbol 13-acetate) treatment of wild-type mice. NF-κB activation either by tumor necrosis factor (TNF)-α or interleukin (IL)-1β was enhanced in Ppp6c-deficient keratinocytes. Overall, we conclude that Ppp6c deficiency predisposes mice to skin carcinogenesis initiated by DMBA. This is the first report showing that such deficiency promotes tumor formation in mice.

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