Regulation of nuclear translocation of HDAC3 by IκBα is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor γ function
Regulation of nuclear translocation of HDAC3 by IκBα is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor γ function
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DOI：
10.1074/jbc.m507784200
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发表时间：
2006-02-17
影响因子：
4.8
通讯作者：
Ye, JP
中科院分区：
文献类型：
--
作者：
Gao, ZG;He, Q;Ye, JP
TNF-α抑制过氧化物酶体增殖物激活受体γ（PPARgamma）功能导致炎症和癌症中的葡萄糖和脂肪酸代谢紊乱，尽管分子机制尚未完全了解。在这项研究中，我们证明HDAC 3的核转位受TNF-α的调节，并且该事件是TNF-α抑制PPAR-γ转录活性所必需的。HDAC 3与细胞质中的I κ B α相关。在I κ B α响应TNF-α降解后，HDAC 3进行核转位，导致细胞核中HDAC 3活性增加。该事件导致HDAC 3的亚细胞再分布。I κ B α的敲除，而不是p65或p50的敲除，导致HDAC 3在细胞质中的消失，这与HDAC 3在细胞核中的富集有关。这些数据表明，TNF-α对PPAR γ的抑制与PPAR γ DNA结合活性的降低无关。相反，这些结果表明HDAC 3的I κ B α依赖性核转位是TNF-α抑制PPAR γ的原因。
dInhibition of peroxisome proliferator-activated receptor gamma (PPAR gamma) function by TNF-alpha contributes to glucose and fatty acid metabolic disorders in inflammation and cancer, although the molecular mechanism is not fully understood. In this study, we demonstrate that nuclear translocation of HDAC3 is regulated by TNF-alpha, and this event is required for inhibition of transcriptional activity of PPAR gamma by TNF-alpha. HDAC3 is associated with I kappa B alpha in the cytoplasm. After I kappa B alpha degradation in response to TNF-alpha, HDAC3 is subject to nuclear translocation, leading to an increase in HDAC3 activity in the nucleus. This event leads to subcellular redistribution of HDAC3. Knock-out of I kappa B alpha, but not p65 or p50, leads to disappearance of HDAC3 in the cytoplasm, which is associated with HDAC3 enrichment in the nucleus. These data suggest that inhibition of PPAR gamma by TNF-alpha is not associated with a reduction in the DNA binding activity of PPAR gamma. Rather, these results suggest that I kappa B alpha-dependent nuclear translocation of HDAC3 is responsible for PPAR gamma inhibition by TNF-alpha.