title: A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation.
abstract: Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response.
authors.affiliation: Animal Models and Cancer Laboratory, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Rosaura
authors.initials: R
authors.lastname: Esteve-Puig
authors.affiliation: Animal Models and Cancer Laboratory, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Gil
authors.affiliation: Animal Models and Cancer Laboratory, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: González-Sánchez
authors.affiliation: Proteomic Laboratory Medical Oncology Research Program, Vall d'Hebron Institute of Oncology - VHIO, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Joan Josep
authors.initials: JJ
authors.lastname: Bech-Serra
authors.affiliation: Animal Models and Cancer Laboratory, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Grueso
authors.affiliation: Pathology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández-Losa
authors.affiliation: Pathology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Moliné
authors.affiliation: Proteomic Laboratory Medical Oncology Research Program, Vall d'Hebron Institute of Oncology - VHIO, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Canals
authors.affiliation: Pathology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Ferrer
authors.affiliation: Clinical Oncology Program, Vall d'Hebron Institute of Oncology - VHIO, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.affiliation: Department of Dermatology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Boris
authors.initials: B
authors.lastname: Bastian
authors.affiliation: Pathology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón Y Cajal
authors.affiliation: Animal Laboratory Unit, Barcelona Biomedical Research Park (PRBB), Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Martín-Caballero
authors.affiliation: Surgery and Medicine Department, Veterinary School, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Juana Maria
authors.initials: JM
authors.lastname: Flores
authors.affiliation: Cancer Genomics Group Translational Research Program, Vall d'Hebron Institute of Oncology - VHIO, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Vivancos
authors.affiliation: Dermatology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Vicenç
authors.initials: V
authors.lastname: García-Patos
authors.affiliation: Animal Models and Cancer Laboratory, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Juan Ángel
authors.initials: JÁ
authors.lastname: Recio
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000528:radiation effects*; D004195:Disease Models, Animal; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008822:Mice, Transgenic; D018307:Neoplasms, Squamous Cell / Q000209:etiology / Q000473:pathology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C553307:HGF protein, mouse; D012097:Repressor Proteins; D017228:Hepatocyte Growth Factor; D011494:Protein Kinases; C470845:NUAK1 protein, human; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases