E1A inhibits transforming growth factor-beta signaling through binding to Smad proteins.
Smads form a recently identified family of proteins that mediate intracellular signaling of the transforming growth factor (TGF)-beta superfamily. Smads bind to DNA and act as transcriptional regulators. Smads interact with a variety of transcription factors, and the interaction is likely to determine the target specificity of gene induction. Smads also associate with transcriptional coactivators such as p300 and CBP. E1A, an adenoviral oncoprotein, inhibits TGF-beta-induced transactivation, and the ability of E1A to bind p300/CBP is required for the inhibition. Here we determined the Smad interaction domain (SID) in p300 and found that two adjacent regions are required for the interaction. One of the regions is the C/H3 domain conserved between p300 and CBP, and the other is a nonconserved region. p300 mutants containing SID inhibit transactivation by TGF-beta in a dose-dependent manner. E1A inhibits the interaction of Smad3 with a p300 mutant that contains SID but lacks the E1A binding domain. We found that E1A interacts specifically with receptor-regulated Smads, suggesting a novel mechanism whereby E1A antagonizes TGF-beta signaling.
Nishihara
A
A
Department of Biochemistry, The Cancer Institute of Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan.
Hanai
J
J
Imamura
T
T
Miyazono
K
K
Kawabata
M
M
D017500:Adenovirus E1A Proteins / Q000502:physiology*; D000595:Amino Acid Sequence; D001483:Base Sequence; D015342:DNA Probes; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D015342:DNA Probes; D004268:DNA-Binding Proteins; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta