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 (Bt(2)cAMP), RA also synergizes with Bt(2)cAMP in enhancing the basal promoter activity when the MMP-2 proximal promoter activity is induced by transient transfection and RA/Bt(2)cAMP 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/Bt(2)cAMP-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. (C) 1999 Academic Press.