Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis
| Autor: | Yui Inoue, Nobuhiro Tanuma, Hiroshi Shima, Toshio Watanabe, Koh Miura, Hiroyuki Kato, Miyuki Nomura, Masami Sato, Yoji Yamashita, Ikuro Sato, Yuki Momoi, Makoto Maemondo, Natsuko Chiba, Koreyuki Kurosawa, Yoichiro Kakugawa, Shigemi Ito, Honami Ogoh, Masato Sakayori, Ryuichi Katakura, Katsuhisa Hayashi |
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| Rok vydání: | 2015 |
| Předmět: |
Keratinocytes
Cancer Research DNA damage Carcinogenesis Ultraviolet Rays Cell Phosphatase DMBA Human skin Apoptosis Biology Gene mutation medicine.disease_cause Histones Mice medicine Skin Squamous Cell Carcinoma Phosphoprotein Phosphatases Animals Cell Proliferation Skin bcl-2-Associated X Protein Mice Knockout integumentary system Caspase 3 Tumor Suppressor Proteins Molecular biology medicine.anatomical_structure Oncology Cancer research Carcinoma Squamous Cell Tumor Suppressor Protein p53 Apoptosis Regulatory Proteins DNA Damage |
| Zdroj: | Cancer letters. 365(2) |
| ISSN: | 1872-7980 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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