ADENOVIRUS E1A FUNCTIONS AS A COFACTOR FOR RETINOIC ACID RECEPTOR-BETA (RAR-BETA) THROUGH DIRECT INTERACTION WITH RAR-BETA

Transcription regulation by DNA-bound activators is thought to be medi ated by a direct interaction between these proteins and TATA-binding p rotein (TBP), TFIIB, or TBP-associated factors, although occasionally cofactors or adapters are required. For ligand-induced activation by t he retinoic acid receptor-retinoid X receptor (RAR-RXR) heterodimer, t he RAR beta 2 promoter is dependent on the presence of E1A or E1A-like activity, since this promoter is activated by retinoic acid only in c ells expressing such proteins. The mechanism underlying this E1A requi rement is largely unknown. We now show that direct interaction between RAR and E1A is a requirement for retinoic acid-induced RAR beta 2 act ivation. The activity of the hormone-dependent activation function 2 ( AF-2) of RAR beta is upregulated by E1A, and an interaction between th is region and E1A was observed, but not with AF-1 or AF-2 of RXR alpha . This interaction is dependent on conserved region LII (CRIII), the 1 3S mRNA-specific region of E1A. Deletion analysis within this region i ndicated that the complete CRIII is needed for activation. The putativ e zinc finger region is crucial, probably as a consequence of interact ion with TBP, Furthermore, the region surrounding amino acid 178, part ially overlapping with the TBP binding region, is involved in both bin ding to and activation by AF-2. We propose that E1A functions as a cof actor by interacting with both TBP and RAR, thereby stabilizing the pr einitiation complex.