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A conditional mouse expressing an activating mutation in NRF2 displays hyperplasia of the upper gastrointestinal tract and decreased white adipose tissue.
Bowman, Brittany M; Montgomery, Stephanie A; Schrank, Travis P; Simon, Jeremy M; Ptacek, Travis S; Tamir, Tigist Y; Mulvaney, Kathleen M; Weir, Seth J; Nguyen, Tuong T; Murphy, Ryan M; Makowski, Liza; Hayes, D Neil; Chen, Xiaoxin L; Randell, Scott H; Weissman, Bernard E; Major, Michael B.
Afiliação
  • Bowman BM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Montgomery SA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Schrank TP; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
  • Simon JM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Ptacek TS; Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Tamir TY; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Mulvaney KM; Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Weir SJ; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Nguyen TT; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Murphy RM; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Makowski L; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Hayes DN; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Chen XL; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Randell SH; Marsico Lung Institute, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Weissman BE; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Major MB; University of Tennessee Health Science Center for Cancer Research, Department of Medicine, Division of Hematology and Oncology, University of Tennessee, Memphis, TN, USA.
J Pathol ; 252(2): 125-137, 2020 10.
Article em En | MEDLINE | ID: mdl-32619021
Activation of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2) transcription factor is a critical and evolutionarily conserved cellular response to oxidative stress, metabolic stress, and xenobiotic insult. Deficiency of NRF2 results in hypersensitivity to a variety of stressors, whereas its aberrant activation contributes to several cancer types, most commonly squamous cell carcinomas of the esophagus, oral cavity, bladder, and lung. Between 10% and 35% of patients with squamous cell carcinomas display hyperactive NRF2 signaling, harboring activating mutations and copy number amplifications of the NFE2L2 oncogene or inactivating mutations or deletions of KEAP1 or CUL3, the proteins of which co-complex to ubiquitylate and degrade NRF2 protein. To better understand the role of NRF2 in tumorigenesis and more broadly in development, we engineered the endogenous Nfe2l2 genomic locus to create a conditional mutant LSL-Nrf2E79Q mouse model. The E79Q mutation, one of the most commonly observed NRF2-activating mutations in human squamous cancers, codes for a mutant protein that does not undergo KEAP1/CUL3-dependent degradation, resulting in its constitutive activity. Expression of NRF2 E79Q protein in keratin 14 (KRT14)-positive murine tissues resulted in hyperplasia of squamous cell tissues of the tongue, forestomach, and esophagus, a stunted body axis, decreased weight, and decreased visceral adipose depots. RNA-seq profiling and follow-up validation studies of cultured NRF2E79Q murine esophageal epithelial cells revealed known and novel NRF2-regulated transcriptional programs, including genes associated with squamous cell carcinoma (e.g. Myc), lipid and cellular metabolism (Hk2, Ppard), and growth factors (Areg, Bmp6, Vegfa). These data suggest that in addition to decreasing adipogenesis, KRT14-restricted NRF2 activation drives hyperplasia of the esophagus, forestomach, and tongue, but not formation of squamous cell carcinoma. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Lesões Pré-Cancerosas / Trato Gastrointestinal Superior / Modelos Animais de Doenças / Fator 2 Relacionado a NF-E2 / Tecido Adiposo Branco / Carcinogênese Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Pathol Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Lesões Pré-Cancerosas / Trato Gastrointestinal Superior / Modelos Animais de Doenças / Fator 2 Relacionado a NF-E2 / Tecido Adiposo Branco / Carcinogênese Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Pathol Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos