title: PTEN positively regulates UVB-induced DNA damage repair.
abstract: 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.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Ming
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Shea
authors.forename: Keyoumars
authors.initials: K
authors.lastname: Soltani
authors.forename: Baozhong
authors.initials: B
authors.lastname: Zhao
authors.forename: Weinong
authors.initials: W
authors.lastname: Han
authors.forename: Robert C
authors.initials: RC
authors.lastname: Smart
authors.forename: Carol S
authors.initials: CS
authors.lastname: Trempus
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: He
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002460:Cell Line / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D015536:Down-Regulation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D055623:Keratosis, Actinic / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010212:Papilloma / Q000209:etiology / Q000235:genetics / Q000473:pathology; D011230:Precancerous Conditions / Q000209:etiology / Q000235:genetics; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; C086984:XPC protein, human; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C494918:AKT1 protein, human; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse