| Project/Area Number |
12670995
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | Nagasaki University |
|---|
Principal Investigator |
MORI Naoki Nagasaki University, Institute of Tropical Medicine, Department of Preventive Medicine Instructor, 熱帯医学研究所, 助手 (10220013)
|
|---|
| Project Period (FY) |
2000 – 2001
|
| Project Status |
Completed (Fiscal Year 2001)
|
| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2000: ¥1,500,000 (Direct Cost: ¥1,500,000)
|
|---|
| Keywords | TGF-β / HTLV-1 Tax / HIV-1 Tat / EBV LMP-1 / Smad / ATL / p300 / CBP / NF-κB / NF-κB / HTLV-1 / Tax |
|---|
| 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.
|
