Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor beta signaling through interaction with CREB-binding protein/p300

Human T-cell leukemia virus type I (HTLV-I) Tax is a potent transcriptional regulator that can activate or repress specific cellular genes and that ha s been proposed to contribute to leukemogenesis in adult T-cell leukemia. P reviously, HTLV-I-infected T-cell clones were found to be resistant to grow th inhibition by transforming growth factor (TGF)-beta, Here it is shown th at Tax can perturb Smad-dependent TGF-beta signaling even though no direct interaction of Tax and Smad proteins could be detected. Importantly, a Intr oduction mutant Tax of CREB-binding protein (CBP)/p300 binding site, could not repress the Smad transactivation function, suggesting that the CBP/p300 binding domain of fax is essential for the suppression of Smad function. B ecause both Tax and Smad are known to interact with CBP/p300 for the potent iation of their transcriptional activities, the effect of CBP/p300 on suppr ession of Smad-mediated transactivation by Tax was examined. Overexpression of CBP/p300 reversed Tax-mediated inhibition of Smad transactivation. Furt hermore, Smad could repress Tax transcriptional activation, indicating reci procal repression between Tax and Smad, These results suggest that Tax inte rferes with the recruitment of CBP/p300 into transcription initiation compl exes on TGF-beta -responsive elements through its binding to CBP/p300, The novel function of Tax as a repressor of TGF-beta signaling may contribute t o HTLV-I leukemogenesis.