Home LiteratureArticle Details
PMID: 21518958 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Molecular and cellular biology ·Vol. 31 ·No. 12 ·2011-06-00 ·Pages 2453-61

Fisher KW, Das B, Kortum RL, Chaika OV, Lewis RE

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.

MeSH Terms
Animals Cells, Cultured Fibroblasts/cytology,drug effects,physiology Gene Expression Regulation/drug effects Genes, ras Humans Mice Mice, Knockout Mitogen-Activated Protein Kinase 1/genetics,metabolism Mitogen-Activated Protein Kinase 3/genetics,metabolism Nitriles/pharmacology Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Protein Kinases/genetics,metabolism Protein Serine-Threonine Kinases/genetics,metabolism Receptors, Estrogen/genetics,metabolism Thiazoles/pharmacology Trans-Activators/genetics,metabolism Transcription Factors ras Proteins/genetics,metabolism
Chemicals
ERRalpha estrogen-related receptor Nitriles Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Ppargc1a protein, mouse Receptors, Estrogen Thiazoles Trans-Activators Transcription Factors XCT790 Protein Kinases KSR-1 protein kinase KSR2 protein, mouse Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 ras Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Fisher Kurt W
Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Das Binita
Kortum Robert L
Chaika Oleg V
Lewis Robert E
References (78)
78 references, click to expand
  1. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity.
    Cell Metab. 2009 Nov;10(5):366-78 PMID: 19883615
  2. Temperature-dependent sex determination in the red-eared slider turtle, Trachemys scripta.
    J Exp Zool. 1998 Aug 1;281(5):409-16 PMID: 9662828
  3. Mitochondrial Complex I decrease is responsible for bioenergetic dysfunction in K-ras transformed cells.
    Biochim Biophys Acta. 2010 Feb;1797(2):314-23 PMID: 19931505
  4. Transcriptional control of mitochondrial biogenesis and function.
    Annu Rev Physiol. 2009;71:177-203 PMID: 19575678
  5. GSEA-P: a desktop application for Gene Set Enrichment Analysis.
    Bioinformatics. 2007 Dec 1;23(23):3251-3 PMID: 17644558
  6. Modulating estrogen receptor-related receptor-alpha activity inhibits cell proliferation.
    J Biol Chem. 2009 Aug 28;284(35):23286-92 PMID: 19546226
  7. Estrogen-related receptor alpha (ERRalpha) inverse agonist XCT-790 induces cell death in chemotherapeutic resistant cancer cells.
    Chem Biol Interact. 2009 Oct 7;181(2):236-42 PMID: 19464277
  8. Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death.
    Cancer Res. 2005 Feb 1;65(3):999-1006 PMID: 15705901
  9. Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1alpha and -2alpha in colon cancer.
    Cancer Res. 2009 Nov 1;69(21):8499-506 PMID: 19843849
  10. Increased OXPHOS activity precedes rise in glycolytic rate in H-RasV12/E1A transformed fibroblasts that develop a Warburg phenotype.
    Mol Cancer. 2009 Jul 31;8:54 PMID: 19646236
  11. Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand.
    Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8912-7 PMID: 15184675
  12. KSR, a novel protein kinase required for RAS signal transduction.
    Cell. 1995 Dec 15;83(6):879-88 PMID: 8521512
  13. KSR stimulates Raf-1 activity in a kinase-independent manner.
    Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):12792-6 PMID: 9371754
  14. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.
    J Clin Oncol. 2008 Dec 10;26(35):5705-12 PMID: 19001320
  15. Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells.
    Am J Physiol Cell Physiol. 2007 Jan;292(1):C125-36 PMID: 16971499
  16. C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1.
    Mol Cell. 2001 Nov;8(5):983-93 PMID: 11741534
  17. Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells.
    J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):106-12 PMID: 19429439
  18. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  19. K-ras mutations and benefit from cetuximab in advanced colorectal cancer.
    N Engl J Med. 2008 Oct 23;359(17):1757-65 PMID: 18946061
  20. Ras, PI(3)K and mTOR signalling controls tumour cell growth.
    Nature. 2006 May 25;441(7092):424-30 PMID: 16724053
  21. The orphan receptors NGFI-B and steroidogenic factor 1 establish monomer binding as a third paradigm of nuclear receptor-DNA interaction.
    Mol Cell Biol. 1993 Sep;13(9):5794-804 PMID: 8395013
  22. KSR2 is a calcineurin substrate that promotes ERK cascade activation in response to calcium signals.
    Mol Cell. 2009 Jun 26;34(6):652-62 PMID: 19560418
  23. The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates adipogenesis.
    Mol Cell Biol. 2005 Sep;25(17):7592-604 PMID: 16107706
  24. Bioenergetic analysis of isolated cerebrocortical nerve terminals on a microgram scale: spare respiratory capacity and stochastic mitochondrial failure.
    J Neurochem. 2009 May;109(4):1179-91 PMID: 19519782
  25. Application of a priori established gene sets to discover biologically important differential expression in microarray data.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15278-9 PMID: 16230612
  26. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells.
    J Cell Biol. 2007 Jul 2;178(1):93-105 PMID: 17606868
  27. The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis.
    Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6472-7 PMID: 15087503
  28. Advances in measuring cellular bioenergetics using extracellular flux.
    Drug Discov Today. 2008 Mar;13(5-6):268-74 PMID: 18342804
  29. Creation of human tumour cells with defined genetic elements.
    Nature. 1999 Jul 29;400(6743):464-8 PMID: 10440377
  30. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene.
    Mol Cell Biol. 1997 Sep;17(9):5400-9 PMID: 9271417
  31. Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice.
    Cancer Res. 2003 Jul 15;63(14):4232-8 PMID: 12874031
  32. Targeting the metabolic flexibility of cancer cells: straighten up and die right.
    Cell Cycle. 2011 Jan 15;10(2):188 PMID: 21239880
  33. The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans.
    Cell. 1995 Dec 15;83(6):903-13 PMID: 8521514
  34. Activation of antioxidant pathways in ras-mediated oncogenic transformation of human surface ovarian epithelial cells revealed by functional proteomics and mass spectrometry.
    Cancer Res. 2004 Jul 1;64(13):4577-84 PMID: 15231669
  35. Activation of Ras cascade increases the mitochondrial enzyme content of respiratory competent yeast.
    Biochem Biophys Res Commun. 2002 May 24;293(5):1383-8 PMID: 12054668
  36. Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha.
    J Med Chem. 2004 Nov 4;47(23):5593-6 PMID: 15509154
  37. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.
    Science. 2009 Sep 18;325(5947):1555-9 PMID: 19661383
  38. Understanding the Warburg effect: the metabolic requirements of cell proliferation.
    Science. 2009 May 22;324(5930):1029-33 PMID: 19460998
  39. Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements.
    Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5992-7 PMID: 15840712
  40. Impairment of mitochondrial respiration in mouse fibroblasts by oncogenic H-RAS(Q61L).
    Cancer Biol Ther. 2010 Jan;9(2):122-33 PMID: 19923925
  41. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity.
    Proc Natl Acad Sci U S A. 2010 May 11;107(19):8788-93 PMID: 20421486
  42. Estrogen-related receptor alpha 1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements.
    Mol Endocrinol. 1997 Mar;11(3):342-52 PMID: 9058380
  43. Emerging roles of E2Fs in cancer: an exit from cell cycle control.
    Nat Rev Cancer. 2009 Nov;9(11):785-97 PMID: 19851314
  44. Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs.
    Mol Cell. 2006 Dec 8;24(5):797-803 PMID: 17157261
  45. A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression.
    J Biol Chem. 2004 Apr 30;279(18):18504-10 PMID: 14978033
  46. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.
    Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18782-7 PMID: 19033189
  47. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  48. Transcriptional control of energy homeostasis by the estrogen-related receptors.
    Endocr Rev. 2008 Oct;29(6):677-96 PMID: 18664618
  49. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease.
    J Clin Invest. 2006 Mar;116(3):615-22 PMID: 16511594
  50. Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression.
    Mol Cell Biol. 1999 Jan;19(1):229-40 PMID: 9858547
  51. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation.
    Oncogene. 2005 Jun 16;24(26):4165-73 PMID: 15806154
  52. A screen for genes that function downstream of Ras1 during Drosophila eye development.
    Genetics. 1996 May;143(1):315-29 PMID: 8722784
  53. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment.
    Nature. 2009 Sep 3;461(7260):109-13 PMID: 19693011
  54. MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1alpha in rasV12 upregulation of VEGF.
    Biochem Biophys Res Commun. 2001 Sep 14;287(1):292-300 PMID: 11549290
  55. Bioenergetic characterization of mouse podocytes.
    Am J Physiol Cell Physiol. 2010 Aug;299(2):C464-76 PMID: 20445170
  56. KSR is a scaffold required for activation of the ERK/MAPK module.
    Genes Dev. 2002 Feb 15;16(4):427-38 PMID: 11850406
  57. Definition of the molecular basis for estrogen receptor-related receptor-alpha-cofactor interactions.
    Mol Endocrinol. 2007 Jan;21(1):62-76 PMID: 17053040
  58. Rethinking the Warburg effect with Myc micromanaging glutamine metabolism.
    Cancer Res. 2010 Feb 1;70(3):859-62 PMID: 20086171
  59. A novel steroidal inhibitor of estrogen-related receptor alpha (ERR alpha).
    Biochem Pharmacol. 2010 Sep 15;80(6):819-26 PMID: 20513360
  60. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha.
    J Biol Chem. 2002 Oct 25;277(43):40265-74 PMID: 12181319
  61. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab.
    Ann Oncol. 2008 Mar;19(3):508-15 PMID: 17998284
  62. Impaired spare respiratory capacity in cortical synaptosomes from Sod2 null mice.
    Free Radic Biol Med. 2011 Apr 1;50(7):866-73 PMID: 21215798
  63. A genetic screen for modifiers of a kinase suppressor of Ras-dependent rough eye phenotype in Drosophila.
    Genetics. 2000 Nov;156(3):1231-42 PMID: 11063697
  64. Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization.
    Mol Cell Biol. 1999 Aug;19(8):5523-34 PMID: 10409742
  65. The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction.
    Cell. 1995 Dec 15;83(6):889-901 PMID: 8521513
  66. The molecular scaffold KSR1 regulates the proliferative and oncogenic potential of cells.
    Mol Cell Biol. 2004 May;24(10):4407-16 PMID: 15121859
  67. Oestrogen-related receptor alpha inverse agonist XCT-790 arrests A549 lung cancer cell population growth by inducing mitochondrial reactive oxygen species production.
    Cell Prolif. 2010 Apr;43(2):103-13 PMID: 20447055
  68. Estrogen-related receptor-gamma and peroxisome proliferator-activated receptor-gamma coactivator-1alpha regulate estrogen-related receptor-alpha gene expression via a conserved multi-hormone response element.
    J Mol Endocrinol. 2005 Apr;34(2):473-87 PMID: 15821111
  69. The oncoprotein H-RasV12 increases mitochondrial metabolism.
    Mol Cancer. 2007 Dec 01;6:77 PMID: 18053146
  70. Kinase suppressor of Ras-1 protects against pulmonary Pseudomonas aeruginosa infections.
    Nat Med. 2011 Mar;17(3):341-6 PMID: 21297617
  71. Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha.
    J Biol Chem. 2004 Nov 19;279(47):49330-7 PMID: 15337744
  72. E2F in vivo binding specificity: comparison of consensus versus nonconsensus binding sites.
    Genome Res. 2008 Nov;18(11):1763-77 PMID: 18836037
  73. Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling.
    Mol Cell Biol. 2000 Aug;20(15):5529-39 PMID: 10891492
  74. Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo.
    Mol Cell Biol. 2002 May;22(9):3035-45 PMID: 11940661
  75. Phosphorylation regulates the nucleocytoplasmic distribution of kinase suppressor of Ras.
    J Biol Chem. 2002 Feb 15;277(7):5369-77 PMID: 11741955
  76. Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes.
    Mol Cancer. 2010 Nov 13;9:293 PMID: 21073737
  77. Oxidative stress and energy crises in neuronal dysfunction.
    Ann N Y Acad Sci. 2008 Dec;1147:53-60 PMID: 19076430
  78. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle.
    Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6570-5 PMID: 15100410
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.05255-11
Published
2011-06-00
Epub
2011-00-25
Pages
2453-61
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC3133429
Subset
IM
Grants
NCI NIH HHS · R01 CA090400 · United States
NCI NIH HHS · R01 CA157774 · United States
NCI NIH HHS · CA90400 · United States
External Links
PubMed source DOI: 10.1128/MCB.05255-11 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2