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: Rosaura Esteve-Puig, Rosa Gil, Elena González-Sánchez, Joan Josep Bech-Serra, Judit Grueso, Javier Hernández-Losa, Teresa Moliné, Francesc Canals, Berta Ferrer, Javier Cortés, Boris Bastian, Santiago Ramón Y Cajal, Juan Martín-Caballero, Juana Maria Flores, Ana Vivancos, Vicenç García-Patos, Juan Ángel Recio
• Journal: PLoS genetics (PLoS Genet) Vol. 10 Issue 10 Pg. e1004721 (Oct 2014) ISSN: 1553-7404 [Electronic] United States
• PMID: 25329316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CDKN1A protein, human
• Cdkn1a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p21
• HGF protein, mouse
• Repressor Proteins
• Hepatocyte Growth Factor
• Protein Kinases
• NUAK1 protein, human
• Protein Serine-Threonine Kinases
• Stk11 protein, mouse
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases
• Animals
• Animals, Newborn
• Apoptosis (genetics, radiation effects)
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• DNA Damage (radiation effects)
• Disease Models, Animal
• Hepatocyte Growth Factor (genetics)
• Humans
• Keratinocytes (metabolism, pathology, radiation effects)
• Mice, Transgenic
• Neoplasms, Squamous Cell (etiology, pathology)
• Phosphorylation
• Protein Kinases (metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Repressor Proteins (metabolism)
• Skin Neoplasms (etiology, genetics, pathology)
• Ultraviolet Rays (adverse effects)