PKR-mediated degradation of STAT1 regulates osteoblast differentiation
PKR-mediated degradation of STAT1 regulates osteoblast differentiation
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DOI：
10.1016/j.yexcr.2009.02.003
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发表时间：
2009-07-15
影响因子：
3.7
通讯作者：
Haneji, Tatsuji
中科院分区：
文献类型：
--
作者：
Yoshida, Kaya;Okamura, Hirohiko;Haneji, Tatsuji
双链RNA依赖性蛋白激酶（PI（R））在包括抗病毒防御、细胞分化、凋亡和肿瘤发生在内的各种生物学反应中起关键作用。在这项研究中，我们研究了PKR是否会影响STAT 1蛋白的翻译后修饰以及这些修饰是否调节成骨细胞分化。我们证明PKR是STAT 1蛋白泛素化所必需的。骨相关基因如I型胶原、整合素结合唾液酸蛋白、骨桥蛋白和osterix的表达在缺乏PKR活性的成骨细胞中受到抑制。与此相反，PKR突变的成骨细胞中白细胞介素6和基质金属蛋白酶8和13的表达增加。STAT 1蛋白的表达和降解受PKR的调控，其调控途径依赖于SLIM。通过RNA干扰抑制SLIM导致成骨细胞中Runx 2的活性降低。IL-6表达的增加和碱性磷酸酶活性的抑制是通过SLIM依赖性途径调节的。而骨相关基因和MMPs的表达受SLIM非依赖性途径调控。我们目前的研究结果表明，PKR的损失诱导的STAT 1蛋白的异常积累调节成骨细胞分化通过SLIM/STAT 1依赖和非依赖途径。(C)2009 Elsevier Inc. All rights reserved.
The double-stranded RNA-dependent protein kinase (PI(R) plays a critical role in various biological responses including antiviral defense, cell differentiation, apoptosis, and tumorigenesis. In this study, we investigated whether PKR could affect the post-translational modifications of STAT1 protein and whether these modifications regulate osteoblast differentiation. We demonstrated that PKR was necessary for the ubiquitination of STAT1 protein. The expressions of bone-related genes such as type I Collagen, integrin binding sialoprotein, osteopontin, and osterix were suppressed in osteoblasts lacking PKR activity. In contrast, the expressions of interleukin-6 and matrix metalloproteinases 8 and 13 increased in PKR-mutated osteoblasts. The expression and degradation of STAT1 protein were regulated by PKR in a SLIM-dependent pathway. Inhibition of SLIM by RNA interference resulted in the decreased activity of Runx2 in osteoblasts. Stimulation of interleukin-6 expression and suppression of alkaline phosphatase activity were regulated through by SLIM-dependent pathway. However, expressions of bone-related genes and MMPs were regulated by SLIM-independent pathway. Our present results suggest that the aberrant accumulation of STAT1 protein induced by loss of PKR regulate osteoblast differentiation through both SLIM/STAT1-dependent and -independent pathways. (C) 2009 Elsevier Inc. All rights reserved.