title: Early Growth Response-1 gene mediates up-regulation of epidermal growth factor receptor expression during hypoxia.
abstract: Hypoxia occurs during development of cancers and is correlated with cancer progression. Hypoxia also induces epidermal growth factor receptor (EGFR) expression. The EGFR plays a vital role in cell growth, and its overexpression can lead to transformation. We sought to determine the regulator(s) of EGFR expression during hypoxia. We demonstrate that early growth response factor 1 (Egr-1), which is induced by hypoxia, can activate the basal transcriptional activity of the EGFR promoter. Egr-1 not only transactivates the EGFR promoter activity but also enhances endogenous EGFR expression. Using a series of EGFR promoter deletion mutants, we show that the region between -484 and -389, which contains a putative Egr-1 consensus motif, is crucial for EGFR transactivation by Egr-1. Electrophoretic mobility shift assays show that Egr-1 binds to the oligonucleotide containing this Egr-1 motif. Also, introduction of an antisense oligonucleotide for Egr-1 diminishes EGFR expression during hypoxia, indicating that the up-regulation of EGFR by hypoxia is mediated through Egr-1. Our results provide evidence that regulation of EGFR promoter activity by Egr-1 represents a mechanism for epidermal cell growth during hypoxia.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute/NIH, Building 37, Room 5002, 37 Convent Drive, Bethesda, MD 20892-4255, USA.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nishi
authors.forename: Katsura H
authors.initials: KH
authors.lastname: Nishi
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Johnson
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051766:Early Growth Response Protein 1; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins; D007624:KB Cells; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D066246:ErbB Receptors