Bone morphogenetic protein 2 opposes Shh-mediated proliferation in cerebellar granule cells through a TIEG-1-based regulation of Nmyc
Bone morphogenetic protein 2 opposes Shh-mediated proliferation in cerebellar granule cells through a TIEG-1-based regulation of Nmyc
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DOI：
10.1074/jbc.m705414200
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发表时间：
2007-12-21
影响因子：
4.8
通讯作者：
Pons, Sebastian
中科院分区：
文献类型：
--
作者：
Alvarez-Rodiguez, Ruben;Barzi, Mercedes;Pons, Sebastian
Nmyc是小脑颗粒神经元前体(CGNPs)细胞周期的重要调节因子，被认为是Sonic hedgehog(Sonic Hedgehog)细胞增殖活性的主要效应因子。Nmyc的异位表达足以促进细胞的自主增殖，并可导致肿瘤的发生。骨形态发生蛋白2(BMP2)通过促进CGNPs的细胞周期退出和分化来拮抗Shh的增殖效应。在这里，我们报告BMP2通过阻断Nmyc的表达来对抗Shh的有丝分裂活性。我们已经确定TIEG-1(KLF10)是通过占据其启动子中的Sp1位点来阻断Nmyc表达的中介因子。我们还证明了TIEG-1在CGNPs中的异位表达诱导了细胞周期停滞，这可以导致细胞凋亡，但不能促进分化。此外，TIEG-1与BMP2活性协同作用，最终分化CGNPs和独立的分化信号，如二丁酰cAMP，并防止TIEG-1受阻细胞的凋亡。综上所述，这些数据强烈表明，BMP2通路作为两个分离但协调的过程触发细胞周期退出和分化，其中TIEG-1作为细胞周期停滞的中介。
Nmyc is a potent regulator of cell cycle in cerebellar granular neuron precursors (CGNPs) and has been proposed to be the main effector of Shh ( Sonic hedgehog) proliferative activity. Nmyc ectopic expression is sufficient to promote cell autonomous proliferation and can lead to tumorigenesis. Bone morphogenetic protein 2 (BMP2) antagonizes Shh proliferative effect by promoting cell cycle exit and differentiation in CGNPs. Here we report that BMP2 opposes Shh mitogenic activity by blocking Nmyc expression. We have identified TIEG-1 (KLF10) as the intermediary factor that blocks Nmyc expression through the occupancy of the Sp1 sites present in its promoter. We also demonstrate that TIEG-1 ectopic expression in CGNPs induces cell cycle arrest that can lead to apoptosis but fails to promote differentiation. Moreover, TIEG-1 synergizes with BMP2 activity to terminally differentiate CGNPs and independent differentiator signals such as dibutyryl cAMP and prevents apoptosis in TIEG-1 arrested cells. All together, these data strongly suggest that the BMP2 pathway triggers cell cycle exit and differentiation as two separated but coordinated processes, where TIEG-1 acts as a mediator of the cell cycle arrest.