Repression of a matrix metalloprotease gene by E1A correlates with its ability to bind to cell type-specific transcription factor AP-2

Abstract

Adenovirus ElA 243-amino acid protein can repress a variety of enhancer-linked viral and cellular promoters. This repression is presumed to be mediated by its interaction with and sequestration of p300, a transcriptional coactivator. Type IV 72-kDa collagenase is one of the matrix metalloproteases that has been implicated in differentiation, development, 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 and that adenovirus E1A 243- amino acid protein represses this promoter by targeting AP-2. Glutathione S-transferase-affinity chromatography studies show that the E1A protein interacts with the DNA binding/ dimerization region of AP-2 and that the N-terminal amino acids of ElA protein are required for this interaction. Further, ElA deletion mutants which do not bind to p300 can repress this collagenase promoter as efficiently as the wildtype ElA protein. Because the AP-2 element is present in a variety of viral and cellular enhancers which are repressed by E1A, these studies suggest that EIA protein can repress cellular and viral promoter/enhancers by forming a complex with cellular transcription factors and that this repression mechanism may be independent of its interaction with p300.