TY - JOUR
T1 - Down syndrome candidate region 1 increases the stability of the IκBα protein
T2 - Implications for its anti-inflammatory effects
AU - Young, Sun Kim
AU - Cho, Kyung Ok
AU - Hong, Joon Lee
AU - Seong, Yun Kim
AU - Sato, Yasufumi
AU - Cho, Young Jin
PY - 2006/12/22
Y1 - 2006/12/22
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M604659200
DO - 10.1074/jbc.M604659200
M3 - Article
C2 - 17062574
AN - SCOPUS:33846019286
SN - 0021-9258
VL - 281
SP - 39051
EP - 39061
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 51
ER -