c-Fos degradation by the ubiquitin-proteasome proteolytic pathway in osteoclast progenitors
c-Fos degradation by the ubiquitin-proteasome proteolytic pathway in osteoclast progenitors
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DOI：
10.1016/j.bone.2005.04.030
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发表时间：
2005-12-01
期刊：
影响因子：
4.1
通讯作者：
Matsumoto, T
中科院分区：
文献类型：
--
作者：
Ito, Y;Inoue, D;Matsumoto, T
c-Fos是属于AP（activator protein）-1转录因子家族的即早基因型原癌基因。基因敲除实验表明，在Fos家族中，只有c-Fos是破骨细胞分化所必需的，但在大多数其他组织和细胞中，c-Fos可以被其他Fos家族成员包括FosB/Delta FosB、Fra-1和Fra-2所取代。为了进一步了解c-Fos在破骨细胞生成中的独特作用，我们研究了破骨细胞分化过程中c-Fos表达的时间分布和调控模式。结果表明，c-Fos蛋白在破骨细胞分化过程中逐渐增加，其程度大于mRNA的诱导。然后，我们确定了c-Fos的蛋白水解途径，赋予不稳定的性质c-Fos蛋白在preosteocytes细胞系，RAW264.7。包括MG 132和Z-LLF在内的蛋白酶体抑制剂在几小时内引起这些细胞中c-Fos蛋白表达的快速增加，但半胱氨酸蛋白酶（E-64）、溶酶体（氯喹）和钙蛋白酶（ALLM）的其他抑制剂则没有。此外，蛋白酶体抑制剂引起广泛的积累的泛素化的c-Fos蛋白和c-Fos蛋白的半衰期延长约三倍。因此，我们得出结论，泛素-蛋白酶体系统是主要的蛋白水解途径赋予不稳定的c-Fos蛋白在前破骨细胞。我们的结果进一步表明，由于泛蛋白蛋白酶体依赖性降解的动态变化而导致的c-Fos稳定可能参与了分化的前破骨细胞中c-Fos蛋白的积累。(c)2005年爱思唯尔公司All rights reserved.
c-Fos is an immediate early gene type proto-oncogene that belongs to the AP (activator protein)-1 transcription factor family. Gene knockout experiments have demonstrated that, among the Fos family, only c-Fos is indispensable for osteoclast differentiation but that c-Fos can be substituted for by other Fos family members including FosB/Delta FosB, Fra-1 and Fra-2, in most other tissues and cells. To further understand a unique role of c-Fos in osteoclastogenesis, we investigated the temporal profile and regulatory mode of expression of c-Fos during the course of osteoclast differentiation. The results indicated that c-Fos protein gradually increased in preosteoclasts during differentiation to a greater extent than that of mRNA induction. We then determined the proteolytic pathway of c-Fos conferring unstable nature on c-Fos protein in a preosteoclastic cell line, RAW264.7. Proteasome inhibitors including MG 132 and Z-LLF caused a rapid increase in c-Fos protein expression in these cells within several hours, but other inhibitors of cysteine protease (E-64), lysosome (chloroquine) and calpain (ALLM) did not. Moreover, the proteasome inhibitors caused an extensive accumulation of ubiquitinated c-Fos protein and an approximately three-fold extension of the c-Fos protein half-life. We therefore conclude that the ubiquitin-proteasome system is the major proteolytic pathway conferring instability on c-Fos protein in preosteoclasts. Our results further imply that c-Fos stabilization due to dynamic changes in the ubiquitin-proteasome-dependent degradation may be involved in the accumulation of c-Fos protein in differentiating preosteoclasts. (c) 2005 Elsevier Inc. All rights reserved.