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Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas.
Todoric, Jelena; Antonucci, Laura; Di Caro, Giuseppe; Li, Ning; Wu, Xuefeng; Lytle, Nikki K; Dhar, Debanjan; Banerjee, Sourav; Fagman, Johan B; Browne, Cecille D; Umemura, Atsushi; Valasek, Mark A; Kessler, Hannes; Tarin, David; Goggins, Michael; Reya, Tannishtha; Diaz-Meco, Maria; Moscat, Jorge; Karin, Michael.
Afiliación
  • Todoric J; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
  • Antonucci L; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Di Caro G; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Li N; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Wu X; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Lytle NK; Departments of Pharmacology and Medicine, Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
  • Dhar D; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Banerjee S; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Fagman JB; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Browne CD; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Umemura A; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 6
  • Valasek MA; Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Kessler H; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Tarin D; Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Goggins M; Departments of Medicine (Gastroenterology) and Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
  • Reya T; Departments of Pharmacology and Medicine, Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
  • Diaz-Meco M; Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • Moscat J; Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • Karin M; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: karinoffic
Cancer Cell ; 32(6): 824-839.e8, 2017 Dec 11.
Article en En | MEDLINE | ID: mdl-29153842
ABSTRACT
Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Proteínas Proto-Oncogénicas c-mdm2 / Factor 2 Relacionado con NF-E2 / Adenocarcinoma in Situ Tipo de estudio: Risk_factors_studies Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2017 Tipo del documento: Article
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Proteínas Proto-Oncogénicas c-mdm2 / Factor 2 Relacionado con NF-E2 / Adenocarcinoma in Situ Tipo de estudio: Risk_factors_studies Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2017 Tipo del documento: Article