Calpain modulates cyclin-dependent kinase inhibitor 1B (p27(Kip1)) in cells of the osteoblast lineage.
Calpain modulates cyclin-dependent kinase inhibitor 1B (p27(Kip1)) in cells of the osteoblast lineage.
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DOI：
10.1007/s00223-011-9491-3
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发表时间：
2011-07
影响因子：
4.2
通讯作者：
Shimada, Masako
中科院分区：
文献类型：
--
作者：
Kashiwagi, Aki;Fein, Mikaela J.;Shimada, Masako
广泛表达的钙蛋白酶-1和-2属于钙依赖性细胞内半胱氨酸蛋白酶家族。两种钙蛋白酶都是由基因Capn 4编码的大催化亚基和小调节亚基组成的异二聚体。钙蛋白酶小亚基的消融消除了钙蛋白酶活性，导致胚胎死亡。我们先前创建了成骨细胞特异性Capn 4基因敲除小鼠，以研究钙蛋白酶小亚基在成骨细胞谱系细胞中的生理作用。Capn 4的缺失减少了骨小梁和皮质骨，主要是由于成骨细胞谱系细胞的增殖和分化受损。为了进一步研究成骨细胞特异性Capn 4基因敲除小鼠发展成骨性骨表型的潜在机制，我们建立了稳定表达对照或Capn 4 RNA干扰（RNAi）的成骨细胞系用于本研究。Capn 4敲除的细胞显示细胞增殖减少，丝氨酸（S）10上总的和磷酸化的细胞周期蛋白依赖性激酶抑制剂1B（p27 Kip 1）的积累，ThreeThrin（T）821上视网膜母细胞瘤蛋白（Rb）的磷酸化减少。此外，Capn 4的消融增加了27 Kip 1 mRNA水平，这可能是由于Akt与蛋白磷酸酶2A（PP 2A）的稳定结合，这可能导致S473上Akt和T32上叉头盒O（FoxO）3A的磷酸化减少。总的来说，钙蛋白酶通过调节成骨细胞中p27 Kip 1的转录和降解来调节细胞增殖功能。总之，钙蛋白酶是成骨细胞系中调节p27 Kip 1的关键调节剂。
The ubiquitously expressed calpains-1 and -2 belong to a family of calcium-dependent intracellular cysteine proteases. Both calpains are heterodimers consisting of a large catalytic subunit and a small regulatory subunit encoded by the gene Capn4. Ablation of the calpain small subunit eliminates calpain activity and leads to embryonic lethality. We previously created osteoblast-specific Capn4 knockout mice to investigate a physiological role for the calpain small subunit in cells of the osteoblast lineage. Deletion of Capn4 reduced trabecular and cortical bone mainly due to impaired proliferation and differentiation of cells of the osteoblast lineage. To further investigate an underlying mechanism by which osteoblast-specific Capn4 knockout mice develop an osteoporotic bone phenotype, we established osteoblastic cell lines stably expressing either control or Capn4 RNA interference (RNAi) for this study. Capn4-knockdown cells showed reduced cell proliferation, accumulation of total and phosphorylated cyclin-dependent kinase inhibitor 1B (p27Kip1) on Serine (S) 10, reduced phosphorylation of retinoblastoma protein (Rb) on Threonine (T) 821. Moreover, ablation of Capn4 increased 27Kip1 mRNA levels likely due to stabilized binding of Akt to protein phosphatase 2A (PP2A), which presumably results in reduced phosphorylation of Akt on S473 and forkhead Box O (FoxO) 3A on T32. Collectively, calpain regulates cell proliferative function by modulating both transcription and degradation of p27Kip1 in osteoblasts. In conclusion, calpain is a critical modulator for regulation of p27Kip1 in cells of the osteoblast lineage.
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影响因子：
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通讯作者：
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