Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor b 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 has been proposed to contribute to leukemogenesis in adult T-cell leukemia. Previously, HTLV-I– infected T-cell clones were found to be resistant to growth inhibition by transforming growth factor (TGF)-b. Here it is shown that Tax can perturb Smad-dependent TGF-b signaling even though no direct interaction of Tax and Smad proteins could be detected. Importantly, a 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 Tax is essential for the suppression of Smad function. Because both Tax and Smad are known to interact with CBP/p300 for the potentiation of their transcriptional activities, the effect of CBP/p300 on suppression of Smad-mediated transactivation by Tax was examined. Overexpression of CBP/p300 reversed Tax-mediated inhibition of Smad transactivation. Furthermore, Smad could repress Tax transcriptional activation, indicating reciprocal repression between Tax and Smad. These results suggest that Tax interferes with the recruitment of CBP/ p300 into transcription initiation complexes on TGF-b–responsive elements through its binding to CBP/p300. The novel function of Tax as a repressor of TGF-b signaling may contribute to HTLV-I leukemogenesis. (Blood.2001;97:2137-2144)