Regulation of Elongation Factor-1α Expression by Growth Factors and Anti-receptor Blocking Antibodies

Amjad H. Talukder, Helle Færk Jørgensen, Mahitosh Mandal, Sandip K. Mishra, Ratna K. Vadlamudi, Brian F.C. Clark, John Mendelsohn, Rakesh Kumar

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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-1α (EF-1α) 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-1α. Both EGF and heregulin-β1 (HRG) induced EF-1α promoter activity and mRNA and protein expression. Growth factor-mediated EF-1α 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-1α 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-1α. Fine mapping and point mutation studies revealed a role of the SP1 site in the observed HRG-mediated regulation of the EF-1α promoter. In addition, we also provide new evidence to suggest that HRG stimulation of the EF-1α promoter involves increased physical interactions with acetylated histone H3 and histone H4. These results suggest that regulation of EF-1α 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-1α expression involve histone acetylation.

Original languageEnglish (US)
Pages (from-to)5636-5642
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number8
DOIs
StatePublished - Feb 23 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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