| Research Abstract |
TGF-β is one of the best-characterized members of growth-inhibitory factors. Previously, it was reported that HTLV-I-infected T-cell clones were resistant to growth inhibition by TGF-β. 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 ATL. Therefore, we investigated whether Tax might block TGF-β signaling. Here it is shown that Tax can perturb Smad-dependent TGF-β signaling even though no direct interaction of Tax and Smad proteins could be detected. Importantly, a mutant Tax of transcription co-activators p300/CBP binding site, could not repress the Smad transactivation function. Overexpression of p300/CBP reversed Tax-mediated inhibition of Smad transactivation. These results suggest that Tax interferes with the recruitment of p300/CBP into transcription initiation complexes on TGF-β-responsive elements through its binding to p300/CBP. We also investigated whether HIV-1 Tat and EBV LMP-1 might block TGF-β signaling. Both proteins inhibit TGF-β-induced transactivation of the responsive promoters. Like Tax, Tat inhibits the ability of the Smads to mediate TGF-β-induced transcriptional activation by interfering with the recruitment of p300/CBP. On the contrary, LMP-1 can not interact with p300/CBP. C-terminal domain of LMP-1 is required for its repressive activity. Inhibition of Smad- dependent TGF-β-responsive promoter activation by LMP-1 is markedly restored by a constitutively active form of the κB inhibitory protein. LMP1 represses the TGF-β signaling through the NF-κB signaling pathway at the transcriptional level by competing for a limiting pool of p300/CBP. The novel function of Tax, Tat, and LMP-1 as repressors of TGF-β signaling may contribute to viral transformation.
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