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MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network.
Elkholi, Rana; Abraham-Enachescu, Ioana; Trotta, Andrew P; Rubio-Patiño, Camila; Mohammed, Jarvier N; Luna-Vargas, Mark P A; Gelles, Jesse D; Kaminetsky, Joshua R; Serasinghe, Madhavika N; Zou, Cindy; Ali, Sumaira; McStay, Gavin P; Pfleger, Cathie M; Chipuk, Jerry Edward.
Afiliação
  • Elkholi R; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn
  • Abraham-Enachescu I; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
  • Trotta AP; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
  • Rubio-Patiño C; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
  • Mohammed JN; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn
  • Luna-Vargas MPA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
  • Gelles JD; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn
  • Kaminetsky JR; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
  • Serasinghe MN; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicin
  • Zou C; Department of Life Sciences, New York Institute of Technology, Northern Boulevard, Old Westbury, NY 11568, USA.
  • Ali S; Department of Life Sciences, New York Institute of Technology, Northern Boulevard, Old Westbury, NY 11568, USA.
  • McStay GP; Department of Life Sciences, New York Institute of Technology, Northern Boulevard, Old Westbury, NY 11568, USA.
  • Pfleger CM; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn
  • Chipuk JE; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicin
Mol Cell ; 74(3): 452-465.e7, 2019 05 02.
Article em En | MEDLINE | ID: mdl-30879903
Signaling diversity and subsequent complexity in higher eukaryotes is partially explained by one gene encoding a polypeptide with multiple biochemical functions in different cellular contexts. For example, mouse double minute 2 (MDM2) is functionally characterized as both an oncogene and a tumor suppressor, yet this dual classification confounds the cell biology and clinical literatures. Identified via complementary biochemical, organellar, and cellular approaches, we report that MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization and inefficiency of oxidative phosphorylation. The MDM2 amino-terminal region is sufficient to bind NDUFS1, alter supercomplex assembly, and induce apoptosis. Finally, this pathway is independent of p53, and several mitochondrial phenotypes are observed in Drosophila and murine models expressing transgenic Mdm2.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína Supressora de Tumor p53 / Estresse Oxidativo / Proteínas Proto-Oncogênicas c-mdm2 / Mitocôndrias / NADH Desidrogenase Limite: Animals / Humans Idioma: En Revista: Mol Cell Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína Supressora de Tumor p53 / Estresse Oxidativo / Proteínas Proto-Oncogênicas c-mdm2 / Mitocôndrias / NADH Desidrogenase Limite: Animals / Humans Idioma: En Revista: Mol Cell Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2019 Tipo de documento: Article