Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5870, USA.
Curr Mol Med. 2012 Sep;12(8):901-16. doi: 10.2174/156652412802480899.
The tumor suppressor p53 is a master regulator of apoptosis and also plays a key role in cell cycle checking. In our previous studies, we demonstrated that p53 directly regulates Bak in mouse JB6 cells (Qin et al. 2008. Cancer Research. 68(11):4150) and that p53-Bak signaling axis plays an important role in mediating EGCG-induced apoptosis. Here, we demonstrate that the same p53-Bak apoptotic signaling axis executes an essential role in regulating lens cell differentiation. First, during mouse lens development, p53 is expressed and differentially phosphorylated at different residues. Associated with p53 expression, Bak is also significantly expressed during mouse lens development. Second, human p53 directly regulates Bak promoter and Bak expression in p53 knockout mice (p53-/-) was significantly downregulated. Third, during in vitro bFGF-induced lens cell differentiation, knockdown of p53 or Bak leads to significant inhibition of lens cell differentiation. Fourth, besides the major distribution of Bak in cytoplasm, it is also localized in the nucleus in normal lens or bFGF-induced differentiating lens cells. Finally, p53 and Bak are co-localized in both cytoplasm and nucleus, and their interaction regulates the stability of p53. Together, these results demonstrate for the first time that the p53-Bak apoptotic signaling axis plays an essential role in regulating lens differentiation.
肿瘤抑制因子 p53 是细胞凋亡的主要调控因子，同时在细胞周期检查中也发挥着关键作用。在我们之前的研究中，我们证明了 p53 可以直接在小鼠 JB6 细胞中调控 Bak（Qin 等人，2008 年。癌症研究。68(11):4150），并且 p53-Bak 信号轴在介导 EGCG 诱导的细胞凋亡中起着重要作用。在这里，我们证明了相同的 p53-Bak 凋亡信号轴在调节晶状体细胞分化中起着重要作用。首先，在小鼠晶状体发育过程中，p53 表达并在不同残基处发生不同程度的磷酸化。与 p53 表达相关，Bak 在小鼠晶状体发育过程中也显著表达。其次，人 p53 可直接调控 Bak 启动子，p53 敲除小鼠（p53-/-）中 Bak 的表达显著下调。第三，在体外 bFGF 诱导的晶状体细胞分化过程中，p53 或 Bak 的敲低导致晶状体细胞分化明显受到抑制。第四，除了 Bak 主要分布在细胞质中外，在正常晶状体或 bFGF 诱导的分化晶状体细胞中，Bak 也定位于细胞核。最后，p53 和 Bak 共定位于细胞质和细胞核中，它们的相互作用调节 p53 的稳定性。总之，这些结果首次证明了 p53-Bak 凋亡信号轴在调节晶状体分化中起着至关重要的作用。
