title: Autophagy controls p38 activation to promote cell survival under genotoxic stress.
abstract: Deregulated cell survival under carcinogen-induced genotoxic stress is vital for cancer development. One of the cellular processes critical for cell survival under metabolic stress and energy starvation is autophagy, a catabolic process involved in capture and delivery of cytoplasmic components to lysosomes for degradation. However, the role of autophagy following carcinogen-induced genotoxic stress remains unclear. Here we show that UVB radiation, a known human skin carcinogen that operates by causing DNA damage, induced autophagy and autophagic flux through AMP kinase activation. Autophagy deficiency sensitizes cells to UVB-induced apoptosis through increasing p62-dependent activation of the stress-activated protein kinase p38. Compared with normal human skin, autophagy was activated in human squamous cell carcinomas, in association with decreased phosphorylation of p38, and increased phosphorylation of ATR and formation of γ-H2AX, two markers of DNA damage response. Our results demonstrate that autophagy promotes cell survival through suppressing p62-mediated p38 activation and thus may facilitate tumor development under genotoxic stress. These findings suggest that autophagy plays an oncogenic role in epithelial carcinogenesis by promoting cell survival.
authors.affiliation: Section of Dermatology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Qiang
authors.forename: Chunli
authors.initials: C
authors.lastname: Wu
authors.forename: Mei
authors.initials: M
authors.lastname: Ming
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: He
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins; D001343:Autophagy / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects*; D002478:Cells, Cultured; D004249:DNA Damage; D004789:Enzyme Activation; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases