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  • Title: Identification of a novel transcriptional regulatory element within the promoter region of the keratinocyte growth factor gene that mediates inducibility to cyclic AMP.
    Author: Zhou J, Finch PW.
    Journal: Biochim Biophys Acta; 1999 Jul 07; 1446(1-2):71-81. PubMed ID: 10395920.
    Abstract:
    Keratinocyte growth factor (KGF) plays a critical role for the normal development and morphogenesis of many different tissues and organs. Furthermore, its expression is induced during wound healing and in various chronic inflammatory diseases. To determine the molecular mechanisms which regulate KGF gene induction at the transcriptional level, we carried out in vitro studies using the human KGF promoter. We have identified a novel regulatory element, TGAGGTCAG, located between -39 and -46 bp (relative to the transcription start site) in the KGF basal promoter region, which binds to inducible transcription factors as determined by electrophoretic mobility shift assay. When cloned in front of a heterologous SV40 promoter this region conferred inducibility to forskolin, a stimulator of adenylate cyclase. In contrast, various mutated forms of this region were either partially or completely impaired in their ability to mediate induction to forskolin. The TGAGGTCAG sequence shared homology to both the cAMP responsive element (CRE) and CCAAT/enhancer binding protein (C/EBP) consensus binding sites. An oligonucleotide comprising a consensus CRE binding site partially competed for the nuclear protein binding to the TGAGGTCAG site. Gel mobility supershift assays indicated that two members of the activating transcription factor (ATF) family of CRE binding proteins, ATF1 and ATF2, were part of the nuclear protein complex bound to this regulatory region. Furthermore, purified recombinant ATF2 was able to directly recognize and bind the TGAGGTCAG sequence. In contrast, no evidence was obtained for C/EBP transcription factors being part of the complex. These results suggest that members of the ATF family are involved in mediating the transcriptional regulation of the KGF gene in response to extracellular stimuli via a novel CRE regulatory element.
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