Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma

Iain H. McKillop, C. M. Schmidt, Paul A. Cahill, James V. Sitzmann

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

The mitogen-activated protein kinase (MAPK) cascade acts as a focal point for signal transduction following activation of both G-protein-linked and tyrosine kinase growth factor receptors. A common intermediate between both of these diverse receptor subtypes includes the small guanosine triphosphate (GTP)-binding protein, p21ras. Point mutations of p21ras have been identified in various tumor types and lead to constitutive activation of this protein and subsequent activation of downstream pathways including the MAPK cascade. Using an in vivo model of hepatocellular carcinoma (HCC), we investigated the abundance and function of individual components of the MAPK cascade and the presence of specific p21ras mutations in this model. Expression of components of the MAPK cascade were determined in tumor and adjacent, non-neoplastic liver specimens by Western blot analysis and functional activity confirmed by substrate phosphorylation assays. Mutations in p21ras were analyzed using an enzyme-linked immunosorbent assay. In tumor, extracellular regulated kinases (ERKs) ERK1, ERK2, and mitogen-activated ERK- regulated kinase-1 (MEK1) were elevated by three- to fourfold as compared with adjacent nontumorigenic normal liver. In contrast, MEK2 was elevated by only 28%. Substrate phosphorylation and detection of phosphorylated ERK1/2 proteins showed increased functional activity of these proteins of the same magnitude as that observed for protein expression. Mutations in p21ras were not detected in this experimental model of HCC. We conclude that HCC is associated with marked changes in expression and function of components of the MAPK cascade independent of common p21ras mutations.

Original languageEnglish (US)
Pages (from-to)1484-1491
Number of pages8
JournalHepatology
Volume26
Issue number6
DOIs
StatePublished - Jan 1 1997

Fingerprint

Mitogen-Activated Protein Kinases
Hepatocellular Carcinoma
Theoretical Models
Mutation
Proteins
Phosphotransferases
Phosphorylation
Neoplasms
Mitogen-Activated Protein Kinase 3
Growth Factor Receptors
Liver
Guanosine Triphosphate
Mitogens
GTP-Binding Proteins
Point Mutation
Protein-Tyrosine Kinases
Signal Transduction
Carrier Proteins
Western Blotting
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Hepatology

Cite this

Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma. / McKillop, Iain H.; Schmidt, C. M.; Cahill, Paul A.; Sitzmann, James V.

In: Hepatology, Vol. 26, No. 6, 01.01.1997, p. 1484-1491.

Research output: Contribution to journalArticle

McKillop, Iain H. ; Schmidt, C. M. ; Cahill, Paul A. ; Sitzmann, James V. / Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma. In: Hepatology. 1997 ; Vol. 26, No. 6. pp. 1484-1491.
@article{454c8ee23bf24530a7c4d2afd3eb37ff,
title = "Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma",
abstract = "The mitogen-activated protein kinase (MAPK) cascade acts as a focal point for signal transduction following activation of both G-protein-linked and tyrosine kinase growth factor receptors. A common intermediate between both of these diverse receptor subtypes includes the small guanosine triphosphate (GTP)-binding protein, p21ras. Point mutations of p21ras have been identified in various tumor types and lead to constitutive activation of this protein and subsequent activation of downstream pathways including the MAPK cascade. Using an in vivo model of hepatocellular carcinoma (HCC), we investigated the abundance and function of individual components of the MAPK cascade and the presence of specific p21ras mutations in this model. Expression of components of the MAPK cascade were determined in tumor and adjacent, non-neoplastic liver specimens by Western blot analysis and functional activity confirmed by substrate phosphorylation assays. Mutations in p21ras were analyzed using an enzyme-linked immunosorbent assay. In tumor, extracellular regulated kinases (ERKs) ERK1, ERK2, and mitogen-activated ERK- regulated kinase-1 (MEK1) were elevated by three- to fourfold as compared with adjacent nontumorigenic normal liver. In contrast, MEK2 was elevated by only 28{\%}. Substrate phosphorylation and detection of phosphorylated ERK1/2 proteins showed increased functional activity of these proteins of the same magnitude as that observed for protein expression. Mutations in p21ras were not detected in this experimental model of HCC. We conclude that HCC is associated with marked changes in expression and function of components of the MAPK cascade independent of common p21ras mutations.",
author = "McKillop, {Iain H.} and Schmidt, {C. M.} and Cahill, {Paul A.} and Sitzmann, {James V.}",
year = "1997",
month = "1",
day = "1",
doi = "10.1002/hep.510260615",
language = "English (US)",
volume = "26",
pages = "1484--1491",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "6",

}

TY - JOUR

T1 - Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma

AU - McKillop, Iain H.

AU - Schmidt, C. M.

AU - Cahill, Paul A.

AU - Sitzmann, James V.

PY - 1997/1/1

Y1 - 1997/1/1

N2 - The mitogen-activated protein kinase (MAPK) cascade acts as a focal point for signal transduction following activation of both G-protein-linked and tyrosine kinase growth factor receptors. A common intermediate between both of these diverse receptor subtypes includes the small guanosine triphosphate (GTP)-binding protein, p21ras. Point mutations of p21ras have been identified in various tumor types and lead to constitutive activation of this protein and subsequent activation of downstream pathways including the MAPK cascade. Using an in vivo model of hepatocellular carcinoma (HCC), we investigated the abundance and function of individual components of the MAPK cascade and the presence of specific p21ras mutations in this model. Expression of components of the MAPK cascade were determined in tumor and adjacent, non-neoplastic liver specimens by Western blot analysis and functional activity confirmed by substrate phosphorylation assays. Mutations in p21ras were analyzed using an enzyme-linked immunosorbent assay. In tumor, extracellular regulated kinases (ERKs) ERK1, ERK2, and mitogen-activated ERK- regulated kinase-1 (MEK1) were elevated by three- to fourfold as compared with adjacent nontumorigenic normal liver. In contrast, MEK2 was elevated by only 28%. Substrate phosphorylation and detection of phosphorylated ERK1/2 proteins showed increased functional activity of these proteins of the same magnitude as that observed for protein expression. Mutations in p21ras were not detected in this experimental model of HCC. We conclude that HCC is associated with marked changes in expression and function of components of the MAPK cascade independent of common p21ras mutations.

AB - The mitogen-activated protein kinase (MAPK) cascade acts as a focal point for signal transduction following activation of both G-protein-linked and tyrosine kinase growth factor receptors. A common intermediate between both of these diverse receptor subtypes includes the small guanosine triphosphate (GTP)-binding protein, p21ras. Point mutations of p21ras have been identified in various tumor types and lead to constitutive activation of this protein and subsequent activation of downstream pathways including the MAPK cascade. Using an in vivo model of hepatocellular carcinoma (HCC), we investigated the abundance and function of individual components of the MAPK cascade and the presence of specific p21ras mutations in this model. Expression of components of the MAPK cascade were determined in tumor and adjacent, non-neoplastic liver specimens by Western blot analysis and functional activity confirmed by substrate phosphorylation assays. Mutations in p21ras were analyzed using an enzyme-linked immunosorbent assay. In tumor, extracellular regulated kinases (ERKs) ERK1, ERK2, and mitogen-activated ERK- regulated kinase-1 (MEK1) were elevated by three- to fourfold as compared with adjacent nontumorigenic normal liver. In contrast, MEK2 was elevated by only 28%. Substrate phosphorylation and detection of phosphorylated ERK1/2 proteins showed increased functional activity of these proteins of the same magnitude as that observed for protein expression. Mutations in p21ras were not detected in this experimental model of HCC. We conclude that HCC is associated with marked changes in expression and function of components of the MAPK cascade independent of common p21ras mutations.

UR - http://www.scopus.com/inward/record.url?scp=0030715557&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030715557&partnerID=8YFLogxK

U2 - 10.1002/hep.510260615

DO - 10.1002/hep.510260615

M3 - Article

C2 - 9397988

AN - SCOPUS:0030715557

VL - 26

SP - 1484

EP - 1491

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 6

ER -