Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis.

Abstract

We previously reported that deficiency in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) predisposes mouse skin tissue to papilloma formation initiated by DMBA. Here, we demonstrate that Ppp6c loss acts as a tumor promoter in UVB-induced squamous cell carcinogenesis. Following UVB irradiation, mice with Ppp6c-deficient keratinocytes showed a higher incidence of skin squamous cell carcinoma than did control mice. Time course experiments showed that following UVB irradiation, Ppp6c-deficient keratinocytes upregulated expression of p53, PUMA, BAX, and cleaved caspase-3 proteins. UVB-induced tumors in Ppp6c-deficient keratinocytes exhibited a high frequency of both p53- and γH2AX-positive cells, suggestive of DNA damage. Epidemiological and molecular data strongly suggest that UVB from sunlight induces p53 gene mutations in keratinocytes and is the primary causative agent of human skin cancers. Our analysis suggests that PP6 deficiency underlies molecular events that drive outgrowth of initiated keratinocytes harboring UVB-induced mutated p53. Understanding PP6 function in preventing UV-induced tumorigenesis could suggest strategies to prevent and treat this condition.

• Authors: Hiroyuki Kato, Koreyuki Kurosawa, Yui Inoue, Nobuhiro Tanuma, Yuki Momoi, Katsuhisa Hayashi, Honami Ogoh, Miyuki Nomura, Masato Sakayori, Yoichiro Kakugawa, Yoji Yamashita, Koh Miura, Makoto Maemondo, Ryuichi Katakura, Shigemi Ito, Masami Sato, Ikuro Sato, Natsuko Chiba, Toshio Watanabe, Hiroshi Shima
• Journal: Cancer letters (Cancer Lett) Vol. 365 Issue 2 Pg. 223-8 (Sep 01 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 26054846 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Histones
• PUMA protein, mouse
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• bcl-2-Associated X Protein
• gamma-H2AX protein, mouse
• Phosphoprotein Phosphatases
• protein phosphatase 6
• Caspase 3

Topics

• Animals
• Apoptosis (radiation effects)
• Apoptosis Regulatory Proteins (biosynthesis)
• Carcinogenesis (genetics, radiation effects)
• Carcinoma, Squamous Cell (genetics)
• Caspase 3 (metabolism)
• Cell Proliferation
• DNA Damage (genetics)
• Histones (biosynthesis)
• Keratinocytes (metabolism)
• Mice
• Mice, Knockout
• Phosphoprotein Phosphatases (genetics)
• Skin (pathology, radiation effects)
• Tumor Suppressor Protein p53 (biosynthesis)
• Tumor Suppressor Proteins (biosynthesis)
• Ultraviolet Rays (adverse effects)
• bcl-2-Associated X Protein (biosynthesis)