CCAAT/enhancer binding protein homologous protein (DDIT3) induces osteoblastic cell differentiation
CCAAT/enhancer binding protein homologous protein (DDIT3) induces osteoblastic cell differentiation
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DOI：
10.1210/en.2003-0868
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发表时间：
2004-04-01
期刊：
影响因子：
4.8
通讯作者：
Canalis, E
中科院分区：
文献类型：
--
作者：
Pereira, RC;Delany, AM;Canalis, E
CCAAT/增强子结合蛋白（C/EBP）同源蛋白（CHOP/DDIT 3）是C/EBP家族转录因子的一员，在细胞存活和分化中起作用。CHOP/DDIT 3与C/EBP结合形成异二聚体，而异二聚体不与共有Cebp形态发生蛋白-2结合。CHOP/DDIT 3过表达对抗脂肪形成，并且没有引起细胞数量的实质性变化。CHOP/DDIT 3过表达没有改变C/EBP α或β mRNA水平，但在培养24天后降低了C/EBP δ。电泳迁移率变化和超迁移分析表明，CHOP/DDIT 3的过表达通过与C/EBPalpha和-β相互作用降低了C/EBP与其共有序列的结合，证实了其显性负作用。此外，CHOP/DDIT 3增强骨形态发生蛋白-2/Smad信号传导。总之，CHOP/DDIT 3增强基质细胞的成骨分化，部分通过与C/EBPalpha和-β相互作用，也通过增强Smad信号。序列，作为显性负抑制剂。CHOP/DDIT 3阻断脂肪生成，我们推测它可以诱导成骨细胞生成。我们研究了组成性CHOP/DDIT 3过表达在逆转录病毒载体转导的小鼠ST-2基质细胞中的作用。ST-2细胞向成骨细胞分化，CHOP/DDIT 3加速并增强矿化结节的出现，以及骨钙素和碱性磷酸酶mRNA的表达，特别是在骨形态发生蛋白-2存在的情况下。CHOP/DDIT 3过表达对抗脂肪形成，并且没有引起细胞数量的实质性变化。CHOP/DDIT 3过表达没有改变C/EBPalpha或-β mRNA水平，但在培养24天后降低了C/EBPalpha。电泳迁移率变化和超迁移分析表明，CHOP/DDIT 3的过表达通过与C/EBPalpha和-β相互作用降低了C/EBP与其共有序列的结合，证实了其显性负作用。此外，CHOP/DDIT 3增强骨形态发生蛋白-2/Smad信号传导。总之，CHOP/DDIT 3增强基质细胞的成骨分化，部分通过与C/EBPalpha和-β相互作用，也通过增强Smad信号。
CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP/DDIT3), a member of the C/EBP family of transcription factors, plays a role in cell survival and differentiation. CHOP/DDIT3 binds to C/EBPs to form heterodimers that do not bind to consensus Cebpmorphogenetic protein-2. CHOP/DDIT3 overexpression opposed adipogenesis, and did not cause substantial changes in cell number. CHOP/DDIT3 overexpression did not modify C/EBPalpha or -beta mRNA levels but decreased C/EBPdelta after 24 d of culture. Electrophoretic mobility shift and supershift assays demonstrated that overexpression of CHOP/DDIT3 decreased the binding of C/EBPs to their consensus sequence by interacting with C/EBPalpha and -beta, confirming its dominant-negative role. In addition, CHOP/DDIT3 enhanced bone morphogenetic protein-2/Smad signaling. In conclusion, CHOP/DDIT3 enhances osteoblastic differentiation of stromal cells, in part by interacting with C/EBPalpha and -beta and also by enhancing Smad signaling. sequences, acting as a dominant-negative inhibitor. CHOP/DDIT3 blocks adipogenesis, and we postulated it could induce osteoblastogenesis. We investigated the effects of constitutive CHOP/DDIT3 overexpression in murine ST-2 stromal cells transduced with retroviral vectors. ST-2 cells differentiated toward osteoblasts, and CHOP/DDIT3 accelerated and enhanced the appearance of mineralized nodules, and the expression of osteocalcin and alkaline phosphatase mRNAs, particularly in the presence of bone morphogenetic protein-2. CHOP/DDIT3 overexpression opposed adipogenesis, and did not cause substantial changes in cell number. CHOP/DDIT3 overexpression did not modify C/EBPalpha or -beta mRNA levels but decreased C/EBPalpha after 24 d of culture. Electrophoretic mobility shift and supershift assays demonstrated that overexpression of CHOP/DDIT3 decreased the binding of C/EBPs to their consensus sequence by interacting with C/EBPalpha and -beta, confirming its dominant-negative role. In addition, CHOP/DDIT3 enhanced bone morphogenetic protein-2/Smad signaling. In conclusion, CHOP/DDIT3 enhances osteoblastic differentiation of stromal cells, in part by interacting with C/EBPalpha and -beta and also by enhancing Smad signaling.