A synergistic interaction of transcription factors AP2 and YB-1 regulates gelatinase A enhancer-dependent transcription.
The matrix metalloproteinase gelatinase A plays a central role in several critical physiologic processes, including angiogenesis, tumor invasion/metastasis, and chronic inflammation. We demonstrate that high level gelatinase A expression is mediated by a unique interaction of two developmentally regulated transcription factors, AP2 and YB-1, within a discrete 40-base pair enhancer element (RE-1) located in the 5'-flanking region of the gelatinase A gene. Electrophoretic mobility shift assay studies and immunoprecipitation experiments confirmed a direct interaction of AP2 with this binding sequence in the form of AP2.YB-1 heteromeric complexes. Binding of AP2.YB-1 complexes to the RE-1 sequence results in the formation of extended single-stranded DNA regions and may stabilize DNA conformational changes. Overexpression of YB-1 and AP2 proteins by gelatinase A synthesizing hepatoma HepG2 cells induced a synergistic increase in the RE-1-mediated transcription of nearly 160-fold. Thus, the transcription of gelatinase A is subject to a previously unrecognized interplay of double (AP2) and single-stranded (YB-1) DNA binding transcription factors to yield a highly regulated pattern of gene expression.
Mertens
P R
PR
Department of Medicine, San Francisco Veterans Administration Medical Center/University of California, San Francisco, California 94121, USA.
Alfonso-Jaume
M A
MA
Steinmann
K
K
Lovett
D H
DH
D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D004247:DNA; D018983:DNA Footprinting; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D018093:Gelatinases / Q000235:genetics*; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000235:genetics*; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D011485:Protein Binding; D012689:Sequence Homology, Nucleic Acid; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051840:Y-Box-Binding Protein 1
D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D004247:DNA; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2