A Mouse Model Uncovers LKB1 as an UVB-Induced DNA Damage Sensor Mediating CDKN1A (p21WAF1/CIP1) Degradation

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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.

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.

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LKB1-dependent signaling pathways.

Dario Alessi, Kei Sakamoto, Jose R. Bayascas (2006)

This review focuses on remarkable recent findings concerning the mechanism by which the LKB1 protein kinase that is mutated in Peutz-Jeghers cancer syndrome operates as a tumor suppressor. We discuss evidence that the cellular localization and activity of LKB1 is controlled through its interaction with a catalytically inactive protein resembling a protein kinase, termed STRAD, and an armadillo repeat-containing protein, named mouse protein 25 (MO25). The data suggest that LKB1 functions as a tumor suppressor by not only inhibiting proliferation, but also by exerting profound effects on cell polarity and, most unexpectedly, on the ability of a cell to detect and respond to low cellular energy levels. Genetic and biochemical findings indicate that LKB1 exerts its effects by phosphorylating and activating 14 protein kinases, all related to the AMP-activated protein kinase. The work described in this review shows how a study of an obscure cancer syndrome can uncover new and important regulatory pathways, relevant to the understanding of multiple human diseases.

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Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung.

Montserrat Sánchez, Manel Esteller, BARRY TRINK … (2002)

Frequent losses of chromosome 19p have recently been observed in sporadic lung adenocarcinomas, targeting the location of a critical tumor suppressor gene. Here we performed fine mapping of the short arm of chromosome 19 and found that the LKB1/STK11 gene mapped in the minimal-deleted region. Because germ-line mutations at LKB1/STK11 result in the Peutz-Jeghers syndrome and an increased risk of cancer, we performed a detailed genetic screen of the LKB1/STK11 gene in lung tumors. We detected a high frequency of somatic alterations (mainly nonsense mutations) in primary lung adenocarcinomas and in lung cancer cell lines. Thus, our findings demonstrate for the first time that LKB1/STK11 inactivation is a very common event and may be integrally involved in the development of sporadic lung adenocarcinoma.

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PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex.

Anindya Dutta, Virginia Amador, K Terai … (2008)

The DNA polymerase delta processivity factor Proliferating Cell Nuclear Antigen (PCNA) promotes the DNA damage-induced degradation of the replication initiation factor Cdt1 via the CRL4(Cdt2) E3 ubiquitin ligase complex. Here we demonstrate that PCNA promotes the ubiquitylation and degradation of the CDK inhibitor p21 in cells irradiated with low dose of ultraviolet (UV) by a similar mechanism. Human cells that are depleted of Cul4, DDB1 (damage-specific DNA-binding protein-1), or the DCAF Cdt2, are deficient in the UV-induced ubiquitylation and degradation of p21. Depletion of mammalian cells of PCNA by siRNA, or mutations in p21 that abrogate PCNA binding, prevent UV-induced p21 ubiquitylation and degradation, indicating that physical binding with PCNA is necessary for the efficient ubiquitylation of p21 via the CRL4(Cdt2) ubiquitin ligase. Cdt2 functions as the substrate recruiting factor for p21 to the rest of the CRL4 ubiquitin ligase complex. The CRL4(Cdt2) E3 ubiquitin ligase ubiquitylates p21 both in vivo and in vitro, and its activity is dependent on the interaction of p21 with PCNA. Finally, we show that the CRL4(Cdt2) and the SCF(Skp2) ubiquitin ligases are redundant with each other in promoting the degradation of p21 during an unperturbed S phase of the cell cycle.

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Author and article information

Contributors

Sharon E. Plon: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Genet

Journal ID (iso-abbrev): PLoS Genet

Journal ID (publisher-id): plos

Journal ID (pmc): plosgen

Title: PLoS Genetics

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Print): 1553-7390

ISSN (Electronic): 1553-7404

Publication date Collection: October 2014

Publication date (Electronic): 16 October 2014

Volume: 10

Issue: 10

Electronic Location Identifier: e1004721

Affiliations

[1 ]Animal Models and Cancer Laboratory, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Spain

[2 ]Proteomic Laboratory Medical Oncology Research Program, Vall d'Hebron Institute of Oncology - VHIO, Hospital Universitari Vall d'Hebron, Barcelona, Spain

[3 ]Pathology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain

[4 ]Clinical Oncology Program, Vall d'Hebron Institute of Oncology - VHIO, Barcelona, Spain

[5 ]Department of Dermatology, University of California San Francisco, San Francisco, California, United States of America

[6 ]Animal Laboratory Unit, Barcelona Biomedical Research Park (PRBB), Barcelona, Spain

[7 ]Surgery and Medicine Department, Veterinary School, Universidad Complutense de Madrid, Madrid, Spain

[8 ]Cancer Genomics Group Translational Research Program, Vall d'Hebron Institute of Oncology - VHIO, Hospital Universitari Vall d'Hebron, Barcelona, Spain

[9 ]Dermatology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain

Baylor College of Medicine, United States of America

Author notes

* E-mail: juan.recio@ 123456vhir.org

The authors have declared that no competing interests exist.

Conceived and designed the experiments: JAR REP JJBS FC. Performed the experiments: REP RG EGS JJBS JG TM JHL BF JC JMC JMF AV JAR. Analyzed the data: REP RG JJBS FC JHL BF JC JMC JMF AV JAR. Contributed reagents/materials/analysis tools: BB JC SRyC VGP. Wrote the paper: JAR.

[¤a]

Current address: Department of Dermatology, University of California San Francisco, San Francisco, California, United States of America

[¤b]

Current address: Gene Expression and Cancer Group Vall d'Hebron Research Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain

[¤c]

Current address: Breast Cancer Group, Centre for Molecular Medicine Norway, Oslo, Norway

[¤d]

Current address: Experimental Therapeutics Group, Hospital Universitari Vall d'Hebron, Barcelona, Spain

Article

Publisher ID: PGENETICS-D-14-01170

DOI: 10.1371/journal.pgen.1004721

PMC ID: 4199501

PubMed ID: 25329316

SO-VID: 80fa2aeb-27b2-403f-baec-6660c2265f46

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 29 April 2014

Date accepted : 30 August 2014

Page count

Pages: 16

Funding

This work has been supported by the Spanish Ministry of Health, Instituto Carlos III grants FIS(PI080653) and FIS(PI1100384)( www.isciii.es/), Fundación Mútua Madrileña and Fundación Segunda Opinión en Oncología (FUSEON) ( www.fuseon.org). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

ScienceOpen disciplines: Genetics

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ScienceOpen disciplines: Genetics

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