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

Abstract

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.

• Authors: K Hayashi, Y Momoi, N Tanuma, A Kishimoto, H Ogoh, H Kato, M Suzuki, Y Sakamoto, Y Inoue, M Nomura, H Kiyonari, M Sakayori, K Fukamachi, Y Kakugawa, Y Yamashita, S Ito, I Sato, A Suzuki, M Nishio, M Suganuma, T Watanabe, H Shima
• Journal: Oncogene (Oncogene) Vol. 34 Issue 35 Pg. 4647-55 (Aug 27 2015) ISSN: 1476-5594 [Electronic] England
• PMID: 25486434 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• 9,10-Dimethyl-1,2-benzanthracene
• Phosphoprotein Phosphatases
• protein phosphatase 6

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Animals
• Carcinogenesis (metabolism)
• Cells, Cultured
• Keratinocytes (enzymology)
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Mice, Transgenic
• NF-kappa B (metabolism)
• Phosphoprotein Phosphatases (genetics, metabolism)
• Signal Transduction
• Skin (enzymology, pathology)
• Skin Neoplasms (chemically induced, enzymology)