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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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ERRalpha Estrogen-Related Receptor
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / physiology
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Gene Expression Regulation / drug effects
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Genes, ras*
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Humans
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Nitriles / pharmacology
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptors, Estrogen / genetics
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Receptors, Estrogen / metabolism*
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Thiazoles / pharmacology
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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Nitriles
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Receptors, Estrogen
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Thiazoles
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Trans-Activators
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Transcription Factors
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XCT790
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Protein Kinases
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KSR-1 protein kinase
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KSR2 protein, mouse
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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ras Proteins