Regulation of the serine proteinase inhibitor (SERPIN) gene alpha 1-antitrypsin: a paradigm for other SERPINs.
alpha 1-antitrypsin (AAT) is the archetypal member of the serine proteinase inhibitor (SERPIN) gene family. AAT is an acute-phase reactant and the plasma concentration increases three- to four-fold during the inflammatory response. In hepatocytes this increase is mediated primarily by the cytokine interleukin-6 (IL-6) via the transcription factor NF-IL6. The AAT gene contains at least two enhancer elements, one at the 5' end of the gene and the other at the 3' end. Functional studies performed in mammalian hepatoma cells (Hep G2) using constructs containing these AAT enhancer regions linked to a reporter gene have demonstrated that the 5' enhancer is dominant under basal conditions and that, following stimulation with IL-6, both enhancers are essential and the 3' enhancer plays a major role. We have identified a mutation associated with lung disease which occurs in the 3' AAT enhancer; the mutation occurs at a binding site for the ubiquitous transcription factor Oct-1. The functional significance of this mutation is a deficient IL-6 response. Using the AAT gene as a model, we describe the interactions which occur between transcription factors within the 3' enhancer and also those which take place between the 5' and 3' enhancers. These studies shed light on the molecular mechanism of the acute-phase response which could possibly be extended to other members of the SERPIN gene family.
Morgan
K
K
Department of Clinical Laboratory Sciences, Queen's Medical Centre, University Hospital, Nottingham, U.K.
Kalsheker
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NA
D000210:Acute-Phase Reaction / Q000235:genetics*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D000515:alpha 1-Antitrypsin / Q000235:genetics*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D009687:Nuclear Proteins; D014157:Transcription Factors; D000515:alpha 1-Antitrypsin