KSR1 and EPHB4 regulate Myc and PGC1β to promote survival of human colon tumors

Jamie L. McCall, Drew Gehring, Beth K. Clymer, Kurt W. Fisher, Binita Das, David Lee Kelly, Hyunseok Kim, Michael A. White, Robert E Lewis

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (erythropoietin-producing hepatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.

Original languageEnglish (US)
Pages (from-to)2246-2261
Number of pages16
JournalMolecular and cellular biology
Volume36
Issue number17
DOIs
StatePublished - Jan 1 2016

Fingerprint

Erythropoietin
Hepatocellular Carcinoma
Colon
Neoplasms
Survival
Colorectal Neoplasms
Protein Biosynthesis
Tumor Cell Line
KSR-1 protein kinase
Cell Survival
Messenger RNA
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

KSR1 and EPHB4 regulate Myc and PGC1β to promote survival of human colon tumors. / McCall, Jamie L.; Gehring, Drew; Clymer, Beth K.; Fisher, Kurt W.; Das, Binita; Kelly, David Lee; Kim, Hyunseok; White, Michael A.; Lewis, Robert E.

In: Molecular and cellular biology, Vol. 36, No. 17, 01.01.2016, p. 2246-2261.

Research output: Contribution to journalArticle

McCall, JL, Gehring, D, Clymer, BK, Fisher, KW, Das, B, Kelly, DL, Kim, H, White, MA & Lewis, RE 2016, 'KSR1 and EPHB4 regulate Myc and PGC1β to promote survival of human colon tumors', Molecular and cellular biology, vol. 36, no. 17, pp. 2246-2261. https://doi.org/10.1128/MCB.00087-16
McCall, Jamie L. ; Gehring, Drew ; Clymer, Beth K. ; Fisher, Kurt W. ; Das, Binita ; Kelly, David Lee ; Kim, Hyunseok ; White, Michael A. ; Lewis, Robert E. / KSR1 and EPHB4 regulate Myc and PGC1β to promote survival of human colon tumors. In: Molecular and cellular biology. 2016 ; Vol. 36, No. 17. pp. 2246-2261.
@article{acc3587a73fd49aa9e5b9fa0fc2f38ec,
title = "KSR1 and EPHB4 regulate Myc and PGC1β to promote survival of human colon tumors",
abstract = "Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (erythropoietin-producing hepatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.",
author = "McCall, {Jamie L.} and Drew Gehring and Clymer, {Beth K.} and Fisher, {Kurt W.} and Binita Das and Kelly, {David Lee} and Hyunseok Kim and White, {Michael A.} and Lewis, {Robert E}",
year = "2016",
month = "1",
day = "1",
doi = "10.1128/MCB.00087-16",
language = "English (US)",
volume = "36",
pages = "2246--2261",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "17",

}

TY - JOUR

T1 - KSR1 and EPHB4 regulate Myc and PGC1β to promote survival of human colon tumors

AU - McCall, Jamie L.

AU - Gehring, Drew

AU - Clymer, Beth K.

AU - Fisher, Kurt W.

AU - Das, Binita

AU - Kelly, David Lee

AU - Kim, Hyunseok

AU - White, Michael A.

AU - Lewis, Robert E

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (erythropoietin-producing hepatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.

AB - Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (erythropoietin-producing hepatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.

UR - http://www.scopus.com/inward/record.url?scp=84983502948&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84983502948&partnerID=8YFLogxK

U2 - 10.1128/MCB.00087-16

DO - 10.1128/MCB.00087-16

M3 - Article

VL - 36

SP - 2246

EP - 2261

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 17

ER -