title: Concerted Action of PGC-1-related Coactivator (PRC) and c-MYC in the Stress Response to Mitochondrial Dysfunction.
abstract: PGC-1-related coactivator (PRC) has a dual function in growth-regulated mitochondrial biogenesis and as a sensor of metabolic stress. PRC induction by mitochondrial inhibitors, intracellular ROS, or topoisomerase I inhibition orchestrates an inflammatory program associated with the adaptation to cellular stress. Activation of this program is accompanied by the coordinate expression of c-MYC, which is linked kinetically to that of PRC in response to multiple stress inducers. Here, we show that the c-MYC inhibitor 10058-F4 blocks the induction of c-MYC, PRC, and representative PRC-dependent stress genes by the respiratory chain uncoupler, carbonyl cyanide m-chlorophenyl hydrazine (CCCP). This result, confirmed by the suppression of PRC induction by c-MYC siRNA silencing, demonstrates a requirement for c-MYC in orchestrating the stress program. PRC steady-state expression was markedly increased upon mutation of two GSK-3 serine phosphorylation sites within the carboxyl-terminal domain. The negative control of PRC expression by GSK-3 was consistent with the phosphor-inactivation of GSK-3β by CCCP and by the induction of PRC by the GSK-3 inhibitor AZD2858. Unlike PRC, which was induced post-translationally through increased protein half-life, c-MYC was induced predominantly at the mRNA level. Moreover, suppression of Akt activation by the Akt inhibitor MK-2206 blocked the CCCP induction of PRC, c-MYC, and representative PRC stress genes, demonstrating a requirement for Akt signaling. MK-2206 also inhibited the phosphor-inactivation of GSK-3β by CCCP, a result consistent with the ability of Akt to phosphorylate, and thereby suppress GSK-3 activity. Thus, PRC and c-MYC can act in concert through Akt-GSK-3 signaling to reprogram gene expression in response to mitochondrial stress.
authors: From the Department of Cell and Molecular Biology, Northwestern Medical School, Chicago, Illinois 60611.
authors: Natalie
authors: N
authors: Gleyzer
authors: From the Department of Cell and Molecular Biology, Northwestern Medical School, Chicago, Illinois 60611 rsc248@northwestern.edu.
authors: Richard C
authors: RC
authors: Scarpulla
mesh_terms: D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D045744:Cell Line, Tumor; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction; D013312:Stress, Physiological; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; C583189:AZD2858; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D013449:Sulfonamides; D013844:Thiazoles; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: gene regulation; metabolism; mitochondria; signaling; stress