Negative regulation of bone morphogenetic protein/Smad signaling by cas-interacting zinc finger protein in osteoblasts
Negative regulation of bone morphogenetic protein/Smad signaling by cas-interacting zinc finger protein in osteoblasts
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DOI：
10.1074/jbc.m203157200
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发表时间：
2002-08-16
影响因子：
4.8
通讯作者：
Noda, M
中科院分区：
文献类型：
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作者：
Shen, ZJ;Nakamoto, T;Noda, M
骨形态发生蛋白（BMP）信号传导调节体轴决定、凋亡和各种类型细胞（包括神经元、肠和骨细胞）的分化。然而，参与这种BMP生物事件调节的分子尚未完全了解。在这里，我们研究了参与钙蛋白相互作用的锌指蛋白（CIZ）在BMP 2诱导的成骨细胞分化的调制。成骨细胞MC 3 T3 E1细胞中CIZ过表达抑制BMP 2增强的碱性磷酸酶、骨钙素和I型胶原基因表达。上游分析显示，CIZ过表达也抑制BMP 2诱导的Cbfa 1 mRNA表达的增强，Cbfa 1是成骨细胞分化的关键转录因子。BMP诱导的Smad 1和Smad 5激活GCCG介导的转录在CIZ过表达的存在下被阻断。在BMP 2不存在的情况下，CIZ单独过表达适度增强了Cbfa 1 mRNA表达的基础水平。CIZ过表达也增强了1.8 kb的Cbfa 1启动子活性的BMP 2的情况下，而它抑制了BMP 2的存在下的启动子活性。最后，CIZ过度表达抑制成骨细胞培养物中矿化结节的形成。这些数据表明，CIZ是一种新型的BMP/Smad信号传导抑制剂。
Bone morphogenetic protein (BMP) signaling regulates body axis determination, apoptosis, and differentiation of various types of cells including neuron, gut, and bone cells. However, the molecules involved in such BMP regulation of biological events have not been fully understood. Here, we examined the involvement of Cas-interacting zinc finger protein (CIZ) in the modulation of BMP2-induced osteoblastic cell differentiation. CIZ overexpression in osteoblastic MC3T3E1 cells suppressed BMP2-enhanced expression of alkaline phosphatase, osteocalcin, and type I collagen genes. Upstream analyses revealed that CIZ overexpression also suppressed BMP2-induced enhancement of the mRNA expression of Cbfa1, which is a critical transcription factor for osteoblastic differentiation. BMP-induced Smad1 and Smad5 activation of GCCG-mediated transcription was blocked in the presence of CIZ overexpression. CIZ overexpression alone in the absence of BMP2 moderately enhanced basal levels of Cbfa1 mRNA expression. CIZ overexpression also enhanced 1.8-kb Cbfa1 promoter activity in the absence of BMP2, whereas it suppressed the promoter activity in the presence of BMP2. Finally, CIZ overexpression suppressed the formation of mineralized nodules in osteoblastic cell cultures. These data indicate that CIZ is a novel type inhibitor of BMP/Smad signaling.