MAMMALIAN-CELL GROWTH CONTROLS REFLECTED THROUGH PROTEIN INTERACTIONS WITH THE ADENOVIRUS E1A GENE-PRODUCTS

The adenovirus early region 1A (E1A) products infiltrate host transcription control pathways by binding directly to key cellular proteins through several distinct protein binding sites. Closely-spaced sites within E1A conserved region 3 bring various promoter-specific transcription factors into close proximity with the TATA binding protein (TBP) through simultaneous binding of TBP and any one of these factors. These activated transcription complexes are exploited to transcribe the remaining viral genes. To replicate in quiescent cells, the virus must additionally take control of transcription factors that regulate cell cycle specific gene expression and host cell DNA Synthesis pathways. Two protein binding sites in E1A mediate these functions. The region 2-specific site activates the cellular transcription factor, E2F. The role of E1A region 2 is to bind negative regulators of E2F, and dissociate them from E2F transcription complexes. As a result of their binding by EIA, several cellular proteins have been recognized as components of E2F complexes. These include the retinoblastoma susceptibility gene product, PRE, as well as pRB-related proteins and cellular cyclins and kinases associated with them. Equally critical for EIA-mediated host cell proliferation is the function of the EIA amino terminal active site. The apparent target of this protein binding site is a large cellular protein designated p300. The protein sequence derived from the recently cloned p300 cDNA suggests that p300 is involved with cyclic AMP responsive pathways. E1A can bind p300 and the PRE related proteins simultaneously, and thus has the potential to promote interactions between them. These genetically manipulatable interactions make the EIA proteins important guides in deciphering the complex transcription network mediating the changing gene expression patterns characteristic of regulated cell growth and differentiation.