title: 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.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan; Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan; Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan.
authors.forename: Koreyuki
authors.initials: K
authors.lastname: Kurosawa
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan; Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanuma
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Momoi
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan; Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Nara, Japan.
authors.forename: Honami
authors.initials: H
authors.lastname: Ogoh
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nomura
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Sakayori
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kakugawa
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Respiratory Medicine, Miyagi Cancer Center, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Maemondo
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Katakura
authors.affiliation: Division of Pathology, Miyagi Cancer Center, Miyagi, Japan.
authors.forename: Shigemi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of General Thoracic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Sato
authors.affiliation: Division of Pathology, Miyagi Cancer Center, Miyagi, Japan.
authors.forename: Ikuro
authors.initials: I
authors.lastname: Sato
authors.affiliation: Department of Cancer Biology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Chiba
authors.affiliation: Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Nara, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan; Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan. Electronic address: shima@med.tohoku.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shima
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D063646:Carcinogenesis / Q000235:genetics / Q000528:radiation effects*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics; D006657:Histones / Q000096:biosynthesis; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D012867:Skin / Q000473:pathology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D014466:Ultraviolet Rays / Q000009:adverse effects*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D051017:Apoptosis Regulatory Proteins; D006657:Histones; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C475961:gamma-H2AX protein, mouse; D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6; D053148:Caspase 3
keywords: PUMA; Protein phosphatase; UV-induced carcinogenesis; apoptosis; p53; γH2AX