| First Author | Ming M | Year | 2011 |
| Journal | Cancer Res | Volume | 71 |
| Issue | 15 | Pages | 5287-95 |
| PubMed ID | 21771908 | Mgi Jnum | J:174190 |
| Mgi Id | MGI:5052186 | Doi | 10.1158/0008-5472.CAN-10-4614 |
| Citation | Ming M, et al. (2011) PTEN Positively Regulates UVB-Induced DNA Damage Repair. Cancer Res 71(15):5287-95 |
| abstractText | 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. (c)2011 AACR. |
