Down syndrome candidate region 1 increases the stability of the IκBα protein -: Implications for its anti-inflammatory effects
Down syndrome candidate region 1 increases the stability of the IκBα protein -: Implications for its anti-inflammatory effects
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DOI：
10.1074/jbc.m604659200
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发表时间：
2006-12-22
影响因子：
4.8
通讯作者：
Cho, Young-Jin
中科院分区：
文献类型：
--
作者：
Kim, Young Sun;Cho, Kyung-Ok;Cho, Young-Jin
唐氏综合征候选区域1（DSCR 1），钙调磷酸酶的内源性抑制剂，抑制参与炎症反应的基因的表达。为了阐明这些抗炎作用的分子基础，我们使用DSCR1.4或其截短突变体（DSCR1.4-（1-133）和DSCR1.4-（134-197））稳定转染的胶质母细胞瘤细胞，分析了DSCR 1在调节NF-κ B反式激活中的作用。DSCR1.4的过表达显著减弱佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）通过钙调神经磷酸酶非依赖性机制诱导的环氧合酶-2（考克斯-2）表达。使用NF-κ B活化的信号传导分子的抑制剂的实验表明NF-κ B负责考克斯-2的诱导。全长和截短的DSCR 1.4降低了NF-κ B的稳态活性以及PMA诱导的NF-κ B的活化，这与考克斯-2诱导的减弱相关。DSCR1.4不影响PMA刺激的I κ B α的磷酸化或降解动力学;然而，DSCR1.4显著降低I κ B α的基础周转率，从而上调其稳态水平。在相同的情况下，敲低内源性DSCR1.4增加了I κ B α的周转率以及考克斯-2诱导。这些结果表明，DSCR 1通过稳定其抑制蛋白I κ B α来减弱NF-κ B介导的转录激活。
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-kappa B 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-kappa B activation showed that NF-kappa B is responsible for the induction of COX-2. Full-length and truncated DSCR1.4 decreased the steady-state activity of NF-kappa B as well as PMA-induced activation of NF-kappa B, which correlated with attenuation of COX-2 induction. DSCR1.4 did not affect the PMA-stimulated phosphorylation or degradation kinetics of I kappa B alpha; however, DSCR1.4 significantly decreased the basal turnover rate of I kappa B alpha and consequently up-regulated its steady-state level. In the same context, knockdown of endogenous DSCR1.4 increased the turnover rate of I kappa B alpha as well as COX-2 induction. These results suggest that DSCR1 attenuates NF-kappa B-mediated transcriptional activation by stabilizing its inhibitory protein, I kappa B alpha.