Mechanisms of transforming growth factor β induced cell cycle arrest in palate development.
Mechanisms of transforming growth factor β induced cell cycle arrest in palate development.
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转化生长因子β在腭发育过程中诱导细胞周期停滞的机制
DOI：
10.1002/jcp.22477
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发表时间：
2011-05
影响因子：
5.6
通讯作者：
Nawshad, Ali
中科院分区：
文献类型：
--
作者：
Iordanskaia, Tatiana;Nawshad, Ali
腭缝的完全解体发生在腭发育的最后阶段，是正常腭发育所必需的。如果腭部内侧缘缝（MES）没有解体，就可能出现腭裂。已经确定转化生长因子（TGF）β在MES崩解期间诱导上皮间充质转化（EMT）和/或凋亡。MES可能在经历转化或凋亡之前停止细胞周期以促进细胞变化，这在以前从未被研究过。本研究旨在探讨对腭部MES崩解至关重要的TGFβ是否能够诱导细胞周期停滞。我们研究了TGFβ1和TGFβ3对MES细胞中p15 ink 4 b活性的影响，TGFβ1和TGFβ3是细胞周期的有效负调控因子。我们惊奇地发现，TGFβ1，而不是TGFβ3，在p15 ink 4 b基因的激活中起主要作用。相反，在TGFβ1成功阻滞细胞周期后，是TGFβ3而不是TGFβ1引起随后的细胞形态发生，如EMT和凋亡。由于TGFβ信号激活Smads，我们通过定点突变分析了p15 ink 4 b小鼠启动子上的三个Smad结合元件（SBE）的作用，发现这些结合位点是功能性的。ChIP检测表明，TGFβ1而不是TGFβ3促进Smad 4与两个5'末端SBE结合，但不促进3'末端SBE结合。因此，TGFβ1和TGFβ3在实现细胞周期停滞和EMT/凋亡中发挥独立但互补的作用，并且细胞周期停滞是后期细胞变化的先决条件。
Immaculate and complete palatal seam disintegration, which takes place at the last phase of palate development, is essential for normal palate development. And in absence of palatal medial edge seam (MES) disintegration, cleft palate may arise. It has been established that Transforming Growth Factor (TGF) β induces both Epithelial Mesenchymal Transition (EMT) and/or apoptosis during MES disintegration. It is likely that MES might cease cell cycle to facilitate cellular changes prior to undergoing transformation or apoptosis, which has never been studied before. This study was designed to explore whether TGFβ, which is crucial for palatal MES disintegration, is capable of inducing cell cycle arrest. We studied the effects of TGFβ1 and TGFβ3, potent negative regulators of the cell cycle, on p15ink4b activity in MES cells. We surprisingly found that TGFβ1, but not TGFβ3, plays a major role in activation of the p15ink4b gene. In contrast, following successful cell cycle arrest by TGFβ1, it is TGFβ3 but not TGFβ1 that causes later cellular morphogenesis, such as EMT and apoptosis. Since TGFβ signaling activates Smads, we analyzed the roles of three Smad binding elements (SBEs) on the p15ink4b mouse promoter by site specific mutagenesis and found that these binding sites are functional. The ChIP assay demonstrated that TGFβ1, not TGFβ3, promotes Smad4 binding to two 5’ terminal SBEs but not the 3’ terminal site. Thus, TGFβ1 and TGFβ3 play separate yet complimentary roles in achieving cell cycle arrest and EMT/apoptosis and cell cycle arrest is a prerequisite for later cellular changes.
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影响因子：
2.5
作者：
Nawshad, Ali
通讯作者：
Nawshad, Ali
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作者：
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