Regulation of elongation factor-1alpha expression by growth factors and anti-receptor blocking antibodies.
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-1alpha (EF-1alpha) 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-1alpha. Both EGF and heregulin-beta1 (HRG) induced EF-1alpha promoter activity and mRNA and protein expression. Growth factor-mediated EF-1alpha 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 p38(MAPK) and MEK, but not phosphatidylinositol 3-kinase, suppressed both constitutive and HRG-induced stimulation of EF-1alpha 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-1alpha. Fine mapping and point mutation studies revealed a role of the SP1 site in the observed HRG-mediated regulation of the EF-1alpha promoter. In addition, we also provide new evidence to suggest that HRG stimulation of the EF-1alpha promoter involves increased physical interactions with acetylated histone H3 and histone H4. These results suggest that regulation of EF-1alpha 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-1alpha expression involve histone acetylation.
Talukder
A H
AH
Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Jorgensen
H F
HF
Mandal
M
M
Mishra
S K
SK
Vadlamudi
R K
RK
Clark
B F
BF
Mendelsohn
J
J
Kumar
R
R
D000107:Acetylation; D019138:Antibodies, Blocking / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D020890:Neuregulin-1 / Q000276:immunology / Q000378:metabolism*; D020648:Peptide Elongation Factor 1 / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D000068878:Trastuzumab
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D006657:Histones; D020890:Neuregulin-1; D020648:Peptide Elongation Factor 1; D016329:Sp1 Transcription Factor; C087230:heregulin beta1; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D000068878:Trastuzumab