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, Santhakumar Manicassamy, Z. Sun, J. S. Duke-Cohan, K. V S Prasad

Research output: Contribution to journalArticle

35 Citations (Scopus)

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

Fingerprint

T-Cell Antigen Receptor
Cell Death
T-Lymphocytes
Jurkat Cells
Homeostasis
Apoptosis
Peripheral Tolerance
Transformed Cell Line
Ligation
Down-Regulation
Extremities
Genes
Neoplasms
Proteins

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Siva-1 negatively regulates NF-κB activity : Effect on T-cell receptor-mediated activation-induced cell death (AICD). / Gudi, R.; Barkinge, J.; Hawkins, S.; Chu, F.; Manicassamy, Santhakumar; Sun, Z.; Duke-Cohan, J. S.; Prasad, K. V S.

In: Oncogene, Vol. 25, No. 24, 08.06.2006, p. 3458-3462.

Research output: Contribution to journalArticle

Gudi, R, Barkinge, J, Hawkins, S, Chu, F, Manicassamy, S, Sun, Z, Duke-Cohan, JS & Prasad, KVS 2006, 'Siva-1 negatively regulates NF-κB activity: Effect on T-cell receptor-mediated activation-induced cell death (AICD)', Oncogene, vol. 25, no. 24, pp. 3458-3462. https://doi.org/10.1038/sj.onc.1209381
Gudi, R. ; Barkinge, J. ; Hawkins, S. ; Chu, F. ; Manicassamy, Santhakumar ; Sun, Z. ; Duke-Cohan, J. S. ; Prasad, K. V S. / Siva-1 negatively regulates NF-κB activity : Effect on T-cell receptor-mediated activation-induced cell death (AICD). In: Oncogene. 2006 ; Vol. 25, No. 24. pp. 3458-3462.
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