A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation

Autor: Ana Vivancos, Juana M. Flores, Rosaura Esteve-Puig, Vicenç García-Patos, Francesc Canals, Santiago Ramón y Cajal, Elena González-Sánchez, Judit Grueso, Rosa Gil, Juan A. Recio, Joan Josep Bech-Serra, Juan Martín-Caballero, Javier Cortes, Javier Hernández-Losa, Berta Ferrer, Boris C. Bastian, Teresa Moliné
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Keratinocytes
Cancer Research
Skin Neoplasms
medicine.medical_treatment
NUAK1
Apoptosis
AMP-Activated Protein Kinases
Bioinformatics
Biochemistry
Skin Aging
0302 clinical medicine
Medicine and Health Sciences
Phosphorylation
skin and connective tissue diseases
Skin Tumors
Cells
Cultured
Genetics (clinical)
0303 health sciences
integumentary system
Hepatocyte Growth Factor
Kinase
3. Good health
030220 oncology & carcinogenesis
Research Article
Cyclin-Dependent Kinase Inhibitor p21
congenital
hereditary
and neonatal diseases and abnormalities
lcsh:QH426-470
Ultraviolet Rays
DNA repair
DNA damage
Mice
Transgenic
Dermatology
Protein Serine-Threonine Kinases
Biology
03 medical and health sciences
Genetics
medicine
Animals
Humans
Neoplasms
Squamous Cell
Molecular Biology
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Biology and life sciences
Growth factor
DNA
medicine.disease
Biochemical Activity
Repressor Proteins
Disease Models
Animal
lcsh:Genetics
Animals
Newborn
Cancer research
Skin cancer
Protein Kinases
Zdroj: PLoS Genetics, Vol 10, Iss 10, p e1004721 (2014)
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: 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.
Author Summary Environmental insults are directly involved in cancer development. In particular, Ultraviolet (UV) radiation has been associated to the acquisition of different types skin cancer and premature skin aging. UV radiation causes modifications in the genetic material of cells (DNA) that if not repaired properly will lead to a mutated DNA (mutated genes) which might trigger the development of cancer. Understanding the molecular basis of the UV-induced DNA damage response is important to elucidate the mechanisms of skin homeostasis and tumorigenesis. Here we provide a UVB-induced skin cancer animal model showing that LKB1 tumor suppressor is also a DNA damage sensor. Importantly, the data suggest that reduced amounts of LKB1 protein in skin could be a risk factor for UV-induced skin carcinogenesis in humans.
Databáze: OpenAIRE
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