REPRESSION OF A MATRIX METALLOPROTEASE GENE BY E1A CORRELATES WITH ITS ABILITY TO BIND TO CELL-TYPE-SPECIFIC TRANSCRIPTION FACTOR AP-2

Adenovirus E1A 243-amino acid protein can repress a variety of enhance r-linked viral and cellular promoters, This repression is presumed to be mediated by its interaction with and sequestration of p300, a trans criptional coactivator. Type IV 72-kDa collagenase Is one of the matri x metalloproteases that has been Implicated in differentiation, develo pment, angiogenesis, and tumor metastasis, We show here that the cell type-specific transcription factor AP-2 is an important transcription factor for the activation of the type IV 72-kDa collagenase promoter a nd that adenovirus E1A 243-amino acid protein represses this promoter by targeting AP-2, Glutathione S-transferase-affinity chromatography s tudies show that the EIA protein interacts with the DNA binding/dimeri zation region of AP-2 and that the N-terminal amino acids of E1A prote in are required for this interaction. Further, EIA deletion mutants wh ich do not bind to p300 can repress this collagenase promoter as effic iently as the wildtype EIA protein, Because the AP-2 element Is presen t in a variety of viral and cellular enhancers which are repressed by E1A, these studies suggest that E1A protein can repress cellular and v iral promoter/enhancers by forming a complex with cellular transcripti on factors and that this repression mechanism may be independent of it s interaction with p300.