Early Growth Response-1 gene mediates up-regulation of epidermal growth factor receptor expression during hypoxia.
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.
Nishi
Hirotaka
H
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute/NIH, Building 37, Room 5002, 37 Convent Drive, Bethesda, MD 20892-4255, USA.
Nishi
Katsura H
KH
Johnson
Alfred C
AC
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
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D066246:ErbB Receptors