E1A inhibits transforming growth factor-beta signaling through binding to Smad proteins

Smads form a recently identified family of proteins that mediate intracellu lar signaling of the transforming growth factor (TGF)-beta superfamily. Sma ds bind to DNA and act as transcriptional regulators. Smads interact with a variety of transcription factors, and the interaction is likely to determi ne the target specificity of gene induction. Smads also associate with tran scriptional coactivators such as p300 and CBP, E1A, an adenoviral oncoprote in, inhibits TGF-beta-induced transactivation, and the ability of E1A to bi nd p300/CBP is required for the inhibition. Here we determined the Smad int eraction domain (SID) in p300 and found that two adjacent regions are requi red for the interaction. One of the regions is the C/H3 domain conserved be tween p300 and CBP, and the other is a nonconserved region. p300 mutants co ntaining SID inhibit transactivation by TGF-beta in a dose-dependent manner , E1A inhibits the interaction of Smad3 with a p300 mutant that contains SL D but lacks the E1A binding domain. We found that E1A interacts specificall y with receptor-regulated Smads, suggesting a novel mechanism whereby ELA a ntagonizes TGF-beta signaling.