Siva-1 negatively regulates NF-kappaB activity: effect on T-cell receptor-mediated activation-induced cell death (AICD).
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Gudi R, Barkinge J, Hawkins S, Chu F, Manicassamy S, Sun Z, Duke-Cohan JS, Prasad KV
Siva-1 negatively regulates NF-kappaB activity: effect on T-cell receptor-mediated activation-induced cell death (AICD).
Oncogene. 2006 Jun 8;25(24):3458-62. Epub 2006 Feb 20.
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- 16491128 [ View in PubMed]
- Abstract
Ligation of TCRs on stimulated T cells leads to activation-induced cell death (AICD) resulting in the downregulation of immune responses, a process essential for T-cell homeostasis. In this study, using transformed T-cell lines such as Jurkat and Do11.10 as cellular models of TCR-mediated AICD, we have demonstrated that the proapoptotic protein Siva-1 is required for TCR-induced apoptosis. Knockdown of Siva-1 rendered T cells specifically resistant to anti-CD3 but not Fas-induced apoptosis. Further, we observed that in Siva-1 knockout Jurkat cells, TCR-mediated activation of the canonical and non-canonical limbs of the NF-kappaB pathway are significantly enhanced as reflected by elevated nuclear levels of p65 and RelB, respectively. In addition, loss of endogenous Siva-1 also resulted in the enhanced expression of NF-kappaB- responsive anti-apoptotic genes such as Bcl-xL and c-FLIP. Interestingly, the c-FLIP(short) was detected only in TCR-ligated Siva-1 knockdown Jurkat cells. These results demonstrate a significant role for endogenous Siva-1, through its inhibitory effect on NF-kappaB activity, in TCR-mediated AICD with implications in peripheral tolerance, T-cell homeostasis and cancer.