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J. Biol. Chem., Vol. 276, Issue 8, 5636-5642, February 23, 2001
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From the Department of Molecular and Cellular Oncology, University
of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 and the
The epidermal growth factor (EGF) family and its
receptors regulate normal and cancerous epithelial cell proliferation,
a process that could be suppressed by anti-receptor blocking
antibodies. Polypeptide elongation factor-1
Regulation of Elongation Factor-1
Expression by Growth
Factors and Anti-receptor Blocking Antibodies*
,, Institute of Molecular and Structural Biology, Aarhus
University, Aarhus, DK-8000, Denmark
(EF-1) is a
multifunctional protein whose levels are positively correlated with the
proliferative state of cells. To identify genes, whose expression may
be modulated by anti-receptor blocking antibodies, we performed a
differential display screening and isolated differentially expressed
cDNAs. Isolates from one clone were 100% identical to human
EF-1. Both EGF and heregulin-
1 (HRG) induced
EF-1 promoter activity and mRNA and protein
expression. Growth factor-mediated EF-1 expression was effectively
blocked by pretreatment with humanized anti-EGF receptor antibody C225
or anti-human epidermal growth factor receptor-2 (HER2) antibody
herceptin. Mutants and pharmacological inhibitors of
p38MAPK and MEK, but not phosphatidylinositol 3-kinase,
suppressed both constitutive and HRG-induced stimulation of
EF-1 promoter activity in MCF-7 cells. Deletion analysis
of the promoter suggested the requirement of the 
393 to 204 region
for growth factor-mediated transcription of EF-1. Fine
mapping and point mutation studies revealed a role of the SP1 site in
the observed HRG-mediated regulation of the EF-1
promoter. In addition, we also provide new evidence to suggest that HRG
stimulation of the EF-1 promoter involves increased
physical interactions with acetylated histone H3 and histone H4. These
results suggest that regulation of EF-1 expression by extracellular
signals that function through human EGF receptor family members that
are widely deregulated in human cancers and that growth factor
regulation of EF-1 expression involve histone acetylation.
*
This work was supported in part by National Institutes of
Health Grants CA80066 and CA65746, by the Breast Cancer Research Program of the University of Texas M. D. Anderson Cancer Center, and
Bristol-Myers Squibb Funds for Biomedical Research (to R. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Member of the Board of Directors of Imclone System Inc. and holds
stock option.
¶
To whom correspondence should be addressed: Dept. of Molecular
and Cellular Oncology, University of Texas M. D. Anderson Cancer Center-108, 1515 Holcombe Blvd., Houston, TX 77030. E-mail:
rkumar@notes.mdacc.tmc.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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