科研之友
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摘要
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 midline epithelial seam (MES) disintegration, cleft palate may arise. It has been established that transforming growth factor (TGF) b 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 TGFb, which is crucial for palatal MES disintegration, is capable of inducing cell cycle arrest. Westudied the effects of TGF beta 1 and TGFb3, potent negative regulators of the cell cycle, on p15ink4b activity in MES cells. We surprisingly found that TGF beta 1, but not TGF beta 3, plays a major role in activation of the p15ink4b gene. In contrast, following successful cell cycle arrest by TGF beta 1, it is TGF beta 3 but not TGF beta 1 that causes later cellular morphogenesis, such as EMT and apoptosis. Since TGFb 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 TGFb1, not TGFb3, promotes Smad4 binding to two 5' terminal SBEs but not the 3' terminal site. Thus, TGFb1 and TGFb3 play separate yet complimentary roles in achieving cell cycle arrest and EMT/apoptosis and cell cycle arrest is a prerequisite for later cellular changes. J. Cell. Physiol. 226: 1415- 1424, 2011.
- 出版日期2011-5
