Siva-1 negatively regulates NF-κB activity: Effect on T-cell receptor-mediated activation-induced cell death (AICD)

R. Gudi, J. Barkinge, S. Hawkins, F. Chu, S. Manicassamy, Z. Sun, J. S. Duke-Cohan, K. V.S. Prasad

Research output: Contribution to journalArticle

36 Scopus citations

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-κB 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-κB- 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-κB activity, in TCR-mediated AICD with implications in peripheral tolerance, T-cell homeostasis and cancer.

Original languageEnglish (US)
Pages (from-to)3458-3462
Number of pages5
JournalOncogene
Volume25
Issue number24
DOIs
StatePublished - Jun 8 2006
Externally publishedYes

Keywords

  • AICD
  • Apoptosis
  • Bcl-xL
  • NF-κB
  • TCR
  • c-FLIP

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Gudi, R., Barkinge, J., Hawkins, S., Chu, F., Manicassamy, S., Sun, Z., Duke-Cohan, J. S., & Prasad, K. V. S. (2006). Siva-1 negatively regulates NF-κB activity: Effect on T-cell receptor-mediated activation-induced cell death (AICD). Oncogene, 25(24), 3458-3462. https://doi.org/10.1038/sj.onc.1209381