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 ERKindependent, regulation of metabolic capacity is mediated through the expression of peroxisome proliferatoractivated receptor gamma coactivator 1␣ (PGC1␣) and estrogen-related receptor ␣ (ERR␣). This KSR1-regulated pathway is essential for the transformation of cells by oncogenic Ras. In mouse embryo fibroblasts (MEFs) expressing H-Ras V12 , ectopic PGC1␣ was sufficient to rescue ERR␣ expression, metabolic capacity, and anchorage-independent growth in the absence of KSR1. The ability of PGC1␣ to promote anchorageindependent growth required interaction with ERR␣, and treatment with an inhibitor of ERR␣ impeded anchorage-independent growth. In contrast to PGC1␣, the expression of constitutively active ERR␣ (CA-ERR␣) was sufficient to enhance metabolic capacity but not anchorage-independent growth in the absence of KSR1. These data reveal KSR1-dependent control of PGC1␣-and ERR␣-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.

AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival

“…We previously identified PGC1␣ and ERR␣ as genes upregulated by KSR1 in an H-Ras V12 -dependent manner (6). Here, we show K-Ras-mediated and KSR1-dependent upregulation of PGC1␤ and ERR␣ in colon tumor cells and tissues.…”

“…However, numerous potent and specific MEK inhibitors have been developed yet have failed to demonstrate single-agent efficacy in cancer treatment (3). As a molecular scaffold of the Raf-MEK-ERK kinase cascade (4,5), kinase suppressor of Ras 1 (KSR1) is necessary and sufficient for Ras V12 -induced tumorigenesis (4), mouse embryo fibroblast (MEF) transformation (5,6), and pancreatic cancer growth (7) but dispensable for normal development (4). KSR1 is overexpressed in endometrial carcinoma and is required for both proliferation and anchorage-independent growth of endometrial cancer cells (8).…”

Kinase Suppressor of Ras 2 (KSR2) Regulates Tumor Cell Transformation via AMPK

“…Extensive studies of the role of KSR1 in cell proliferation and oncogenic potential have been performed, but little is known about the regulation of these cell fates by KSR2. Previous work in our laboratory used KSR1 Ϫ/Ϫ MEFs to characterize KSR1 function (12,(29)(30)(31). MEFs do not express KSR2 mRNA or protein, making KSR1 Ϫ/Ϫ MEFs effectively doubly null for KSR1 and KSR2 (29).…”

“…KSR2 Ϫ/Ϫ mice exhibit lower expression levels of genes that coordinate OXPHOS, including the transcription fac- tor PGC-1␣ (6). KSR1 is required for Ras V12 -mediated upregulation of PGC-1␣ and ERR␣, which maximizes glycolytic and OXPHOS capacity in MEFs (12). AMPK has been implicated in the regulation of mitochondrial biogenesis and OXPHOS by inducing PGC-1␣ transcriptional activity (21,56,64).…”

“…KSR2 interacts with all AMPK subunits and promotes AMPK phosphorylation in vitro and in vivo (6). KSR1 mediates the Ras-dependent upregulation of peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC1␣) and estrogenrelated receptor ␣ (ERR␣), transcription factors that regulate mitochondrial biogenesis in MEFs, and is essential to promote anchorage-independent growth (12).…”