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A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice.
Quach, Christine; Song, Ying; Guo, Hongrui; Li, Shun; Maazi, Hadi; Fung, Marshall; Sands, Nathaniel; O'Connell, Douglas; Restrepo-Vassalli, Sara; Chai, Billy; Nemecio, Dali; Punj, Vasu; Akbari, Omid; Idos, Gregory E; Mumenthaler, Shannon M; Wu, Nancy; Martin, Sue Ellen; Hagiya, Ashley; Hicks, James; Cui, Hengmin; Liang, Chengyu.
Afiliación
  • Quach C; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Song Y; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Guo H; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Li S; College of Veterinary Medicine, Sichuan Agriculture University, Chengdu, 611130, China.
  • Maazi H; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Fung M; Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
  • Sands N; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • O'Connell D; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Restrepo-Vassalli S; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Chai B; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Nemecio D; USC Michelson Center for Convergent Bioscience, Bridge Institute, University of Southern California, Los Angeles, CA, 90089, USA.
  • Punj V; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Akbari O; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Idos GE; Department of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Mumenthaler SM; Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Wu N; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
  • Martin SE; Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Hagiya A; Norris Comprehensive Cancer Center Transgenic/Knockout Rodent Core Facility, University of Southern California, Los Angeles, CA, 90089, USA.
  • Hicks J; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Cui H; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Liang C; USC Michelson Center for Convergent Bioscience, Bridge Institute, University of Southern California, Los Angeles, CA, 90089, USA.
Nat Commun ; 10(1): 5681, 2019 12 12.
Article en En | MEDLINE | ID: mdl-31831743
ABSTRACT
Aberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAGFS. To investigate the role of UVRAGFS in vivo, we generated mutant mice that inducibly express UVRAGFS (iUVRAGFS). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAGFS mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAGFS mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant ß-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Proteínas Supresoras de Tumor / Carcinogénesis / Inflamación / Mutación Tipo de estudio: Risk_factors_studies Límite: Animals Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Proteínas Supresoras de Tumor / Carcinogénesis / Inflamación / Mutación Tipo de estudio: Risk_factors_studies Límite: Animals Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos