TY - JOUR
T1 - Kinase suppressor of ras 1 (KSR1) regulates PGC1α and estrogen-related receptor α to promote oncogenic ras-dependent anchorage-independent growth
AU - Fisher, Kurt W.
AU - Das, Binita
AU - Kortum, Robert L.
AU - Chaika, Oleg V.
AU - Lewis, Robert E.
PY - 2011/6
Y1 - 2011/6
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=79958035502&partnerID=8YFLogxK
U2 - 10.1128/MCB.05255-11
DO - 10.1128/MCB.05255-11
M3 - Article
C2 - 21518958
AN - SCOPUS:79958035502
SN - 0270-7306
VL - 31
SP - 2453
EP - 2461
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 12
ER -