Down syndrome candidate region 1 increases the stability of the IκBα protein: Implications for its anti-inflammatory effects

Sun Kim Young, Kyung Ok Cho, Joon Lee Hong, Yun Kim Seong, Yasufumi Sato, Young Jin Cho

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Down syndrome candidate region 1 (DSCR1), an endogenous inhibitor of calcineurin, inhibits the expression of genes involved in the inflammatory response. To elucidate the molecular basis of these anti-inflammatory effects, we analyzed the role of DSCR1 in the regulation of NF-κB transactivation using glioblastoma cells stably transfected with DSCR1.4 or its truncation mutants (DSCR1.4-(1-133) and DSCR1.4-(134-197)). Overexpression of DSCR1.4 significantly attenuated the induction of cyclooxygenase-2 (COX-2) expression by phorbol 12-myristate 13-acetate (PMA) via a calcineurin-independent mechanism. Experiments using inhibitors of the signaling molecules for NF-κB activation showed that NF-κB is responsible for the induction of COX-2. Full-length and truncated DSCR1.4 decreased the steady-state activity of NF-κB as well as PMA-induced activation of NF-κB, which correlated with attenuation of COX-2 induction. DSCR1.4 did not affect the PMA-stimulated phosphorylation or degradation kinetics of IκBα; however, DSCR1.4 significantly decreased the basal turnover rate of IκBα and consequently up-regulated its steady-state level. In the same context, knockdown of endogenous DSCR1.4 increased the turnover rate of IκBα as well as COX-2 induction. These results suggest that DSCR1 attenuates NF-κB-mediated transcriptional activation by stabilizing its inhibitory protein, IκBα.

Original languageEnglish
Pages (from-to)39051-39061
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number51
DOIs
Publication statusPublished - 2006 Dec 22

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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