PTEN Positively Regulates UVB-Induced DNA Damage Repair
| Autor: | Carol S. Trempus, Mei Ming, Li Feng, Baozhong Zhao, Keyoumars Soltani, Weinong Han, Yu-Ying He, Christopher R. Shea, Robert C. Smart |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Keratinocytes
Cancer Research Neoplasms Radiation-Induced Skin Neoplasms Xeroderma pigmentosum DNA Repair Ultraviolet Rays DNA damage DNA repair Down-Regulation Human skin Protein Serine-Threonine Kinases medicine.disease_cause p38 Mitogen-Activated Protein Kinases Article Cell Line Mice medicine Animals Humans PTEN CHEK1 RNA Small Interfering skin and connective tissue diseases Papilloma integumentary system biology PTEN Phosphohydrolase medicine.disease Molecular biology DNA-Binding Proteins Keratosis Actinic Checkpoint Kinase 2 Oncology Checkpoint Kinase 1 Carcinoma Squamous Cell biology.protein Cancer research Skin cancer Carcinogenesis Precancerous Conditions Protein Kinases Proto-Oncogene Proteins c-akt DNA Damage |
| Zdroj: | Cancer Research. 71:5287-5295 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Nonmelanoma skin cancer is the most common cancer in the United States, where DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor. However, the critical genetic targets of UVB radiation are undefined. Here we show that attenuating PTEN in epidermal keratinocytes is a predisposing factor for UVB-induced skin carcinogenesis in mice. In skin papilloma and squamous cell carcinoma (SCC), levels of PTEN were reduced compared with skin lacking these lesions. Likewise, there was a reduction in PTEN levels in human premalignant actinic keratosis and malignant SCCs, supporting a key role for PTEN in human skin cancer formation and progression. PTEN downregulation impaired the capacity of global genomic nucleotide excision repair (GG-NER), a critical mechanism for removing UVB-induced mutagenic DNA lesions. In contrast to the response to ionizing radiation, PTEN downregulation prolonged UVB-induced growth arrest and increased the activation of the Chk1 DNA damage pathway in an AKT-independent manner, likely due to reduced DNA repair. PTEN loss also suppressed expression of the key GG-NER protein xeroderma pigmentosum C (XPC) through the AKT/p38 signaling axis. Reconstitution of XPC levels in PTEN-inhibited cells restored GG-NER capacity. Taken together, our findings define PTEN as an essential genomic gatekeeper in the skin through its ability to positively regulate XPC-dependent GG-NER following DNA damage. Cancer Res; 71(15); 5287–95. ©2011 AACR. |
| Databáze: | OpenAIRE |
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