Akt-1 Mediates Survival of Chondrocytes From Endoplasmic Reticulum-induced Stress
Akt-1 Mediates Survival of Chondrocytes From Endoplasmic Reticulum-induced Stress
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DOI：
10.1002/jcp.22001
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发表时间：
2010-03-01
影响因子：
5.6
通讯作者：
Ali, Hydar
中科院分区：
文献类型：
--
作者：
Price, Jeremy;Zaidi, Asifa K.;Ali, Hydar
未折叠蛋白反应（UPR）是一种进化上保守的适应性机制，允许细胞对内质网（ER）应激条件做出反应和调整。除了UPR，磷脂酰肌醇3-激酶（PI 3 K）/Akt和细胞外信号调节激酶（ERK）信号通路保护各种细胞免受ER应激。本研究的目的是评估软骨细胞对内质网应激的敏感性，并确定参与其生存的信号通路。我们发现，低浓度的毒胡萝卜素（10 nM）降低了软骨细胞系（N1511细胞）的活力，这些细胞对毒胡萝卜素诱导的应激的敏感性比成纤维细胞高100倍。有趣的是，在毒胡萝卜素和衣霉素应激的软骨细胞中，促凋亡转录因子CHOP的诱导先于抗凋亡BiP的诱导12 h。虽然这两种药物都引起持续的Akt和ERK磷酸化，但抑制Akt磷酸化使软骨细胞对ER应激敏感，而U 0126阻断ERK信号传导则没有影响。我们发现，Akt-1，而不是Akt-2或Akt-3，主要在N1511软骨细胞中表达。此外，siRNA介导的Akt-1敲低使软骨细胞对ER应激敏感，这与capsase-3活性增加和Bcl（XL）表达降低有关。这些数据表明，在内质网应激条件下，多种信号转导过程调节软骨细胞的生存-死亡决定。因此，CHOP的快速上调可能导致软骨细胞死亡，而Akt-1介导的caspase 3失活和Bcl（XL）的诱导促进存活。J.细胞。222：502-508，2010。(C)2009 Wiley-Liss，Inc.
The unfolded protein response (UPR) is an evolutionary conserved adaptive mechanism that permits cells to react and adjust to conditions of endoplasmic reticulum (ER) stress. In addition to UPR, phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal regulated kinase (ERK) signaling pathways protect a variety of cells from ER stress. The goal of the present study was to assess the susceptibility of chondrocytes to ER stress and to determine the signaling pathways involved in their survival. We found that low concentration of thapsigargin (10 nM) reduced the viability of a chondrocyte cell line (N1511 cells) and that these cells were similar to 100 fold more susceptible to thapsigargin-induced stress than fibroblasts. Interestingly, in thapsigargin and tunicamycin-stressed chondrocytes induction of the proapoptotic transcription factor CHOP preceded that of the anti-apoptotic BiP by 12 h. Although both of these agents caused sustained Akt and ERK phosphorylation; inhibition of Akt phosphorylation sensitized chondrocytes to ER stress, while blocking ERK signaling by U0126 had no effect. We found that Akt-1, but not Akt-2 or Akt-3, is predominantly expressed in N1511 chondrocytes. Furthermore, siRNA-mediated knockdown of Akt-1 sensitized chondrocytes to ER stress, which was associated with increased capsase-3 activity and decreased Bcl(XL) expression. These data suggest that under condition of ER stress, multiple signaling processes regulate chondrocyte's survival-death decisions. Thus, rapid upregulation of CHOP likely contributes to chondrocyte death, while Akt-1-mediated inactivation of caspase 3 and induction of Bcl(XL) promotes survival. J. Cell. Physiol. 222: 502-508, 2010. (C) 2009 Wiley-Liss, Inc.