Retinoic acid synergizes with cyclic AMP to enhance MMP-2 basal promoter activity.
Matrix metalloproteinase-2 (MMP-2) degrades basement membrane collagen and its abnormal expression is associated with the enhanced malignancy of metastasizing cancer cells. Retinoids and cyclic AMP analogs have been shown to affect MMP-2 production. Here we demonstrate that the expression of the human MMP-2 gene is enhanced by a synergistic action of retinoic acid (RA) and dibutyryl cyclic AMP (Bt2cAMP). RA also synergizes with Bt2cAMP in enhancing the basal promoter activity when the MMP-2 proximal promoter activity is induced by transient transfection and RA/Bt2cAMP treatment in human fibrosarcoma HT1080 cells. Deletions beyond -315 bp from the transcription initiation site drastically reduce the synergistic enhancement. A search for a cis-element in the MMP-2 proximal promoter shows the presence of a CRE-like sequence (TGACGTCCC) at position -292 bp in the opposite strand. The CRE-like sequence makes complexes with two DNA binding proteins. The results demonstrate that the RA/Bt2cAMP-enhanced transcription of the MMP-2 gene is dependent on the general transcription machinery and suggest that the basal promoter may be a potential target for gene-specific activators.
D001483:Base Sequence; D003994:Bucladesine / Q000494:pharmacology*; D002460:Cell Line; D003001:Cloning, Molecular; D004357:Drug Synergism; D018093:Gelatinases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000235:genetics*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*