title: Kinase suppressor of ras 1 (KSR1) regulates PGC1α and estrogen-related receptor α to promote oncogenic Ras-dependent anchorage-independent growth.
abstract: Kinase suppressor of ras 1 (KSR1) is a molecular scaffold of the Raf/MEK/extracellular signal-regulated kinase (ERK) cascade that enhances oncogenic Ras signaling. Here we show KSR1-dependent, but ERK-independent, regulation of metabolic capacity is mediated through the expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) and estrogen-related receptor α (ERRα). This KSR1-regulated pathway is essential for the transformation of cells by oncogenic Ras. In mouse embryo fibroblasts (MEFs) expressing H-Ras(V12), ectopic PGC1α was sufficient to rescue ERRα expression, metabolic capacity, and anchorage-independent growth in the absence of KSR1. The ability of PGC1α to promote anchorage-independent growth required interaction with ERRα, and treatment with an inhibitor of ERRα impeded anchorage-independent growth. In contrast to PGC1α, the expression of constitutively active ERRα (CA-ERRα) was sufficient to enhance metabolic capacity but not anchorage-independent growth in the absence of KSR1. These data reveal KSR1-dependent control of PGC1α- and ERRα-dependent pathways that are necessary and sufficient for signaling by oncogenic H-Ras(V12) to regulate metabolism and anchorage-independent growth, providing novel targets for therapeutic intervention.
authors.affiliation: Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Fisher
authors.forename: Binita
authors.initials: B
authors.lastname: Das
authors.forename: Robert L
authors.initials: RL
authors.lastname: Kortum
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Chaika
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lewis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009570:Nitriles; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011960:Receptors, Estrogen; D013844:Thiazoles; D015534:Trans-Activators; D014157:Transcription Factors; D018631:ras Proteins; D000097983:ERRalpha Estrogen-Related Receptor; C485290:Ppargc1a protein, mouse; C488234:XCT790; C097199:KSR-1 protein kinase; C542241:KSR2 protein, mouse