Kinase suppressor of ras 1 (KSR1) regulates PGC1α and estrogen-related receptor α to promote oncogenic ras-dependent anchorage-independent growth

Kurt W. Fisher, Binita Das, Robert L. Kortum, Oleg V. Chaika, Robert E Lewis

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Kinase suppressGrowthor 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 ERKindependent, regulation of metabolic capacity is mediated through the expression of peroxisome proliferatoractivated 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-RasV12, 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 anchorageindependent 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 (CAERR α) 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-RasV12 to regulate metabolism and anchorage-independent growth, providing novel targets for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)2453-2461
Number of pages9
JournalMolecular and cellular biology
Volume31
Issue number12
DOIs
StatePublished - Jun 1 2011

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Estrogen Receptors
Growth
Peroxisomes
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Phosphotransferases
Embryonic Structures
Fibroblasts
KSR-1 protein kinase
ERRalpha estrogen-related receptor
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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Kinase suppressor of ras 1 (KSR1) regulates PGC1α and estrogen-related receptor α to promote oncogenic ras-dependent anchorage-independent growth. / Fisher, Kurt W.; Das, Binita; Kortum, Robert L.; Chaika, Oleg V.; Lewis, Robert E.

In: Molecular and cellular biology, Vol. 31, No. 12, 01.06.2011, p. 2453-2461.

Research output: Contribution to journalArticle

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