The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Cell Death Dis. 2011 Oct 13;2(10):e217. doi: 10.1038/cddis.2011.100.
During eye development, apoptosis is vital to the maturation of highly specialized structures such as the lens and retina. Several forms of apoptosis have been described, including anoikis, a form of apoptosis triggered by inadequate or inappropriate cell-matrix contacts. The anoikis regulators, Bit1 (Bcl-2 inhibitor of transcription-1) and protein kinase-D (PKD), are expressed in developing lens when the organelles are present in lens fibers, but are downregulated as active denucleation is initiated. We have previously shown that in rats with a spontaneous mutation in the Cryba1 gene, coding for βA3/A1-crystallin, normal denucleation of lens fibers is inhibited. In rats with this mutation (Nuc1), both Bit1 and PKD remain abnormally high in lens fiber cells. To determine whether βA3/A1-crystallin has a role in anoikis, we induced anoikis in vitro and conducted mechanistic studies on astrocytes, cells known to express βA3/A1-crystallin. The expression pattern of Bit1 in retina correlates temporally with the development of astrocytes. Our data also indicate that loss of βA3/A1-crystallin in astrocytes results in a failure of Bit1 to be trafficked to the Golgi, thereby suppressing anoikis. This loss of βA3/A1-crystallin also induces insulin-like growth factor-II, which increases cell survival and growth by modulating the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR and extracellular signal-regulated kinase pathways. We propose that βA3/A1-crystallin is a novel regulator of both life and death decisions in ocular astrocytes.
在眼睛发育过程中，细胞凋亡对于高度特化结构（如晶状体和视网膜）的成熟至关重要。已经描述了几种形式的细胞凋亡，包括失巢凋亡，这是一种由细胞-基质接触不足或不当触发的细胞凋亡形式。失巢凋亡调节因子 Bit1（转录因子-1 的 Bcl-2 抑制剂）和蛋白激酶-D（PKD）在细胞器存在于晶状体纤维中的晶状体发育过程中表达，但在主动去核开始时下调。我们之前已经表明，在 Cryba1 基因自发突变的大鼠中，该基因编码βA3/A1-晶体蛋白，正常的晶状体纤维去核被抑制。在具有该突变（Nuc1）的大鼠中，Bit1 和 PKD 在晶状体纤维细胞中仍然异常高。为了确定βA3/A1-晶体蛋白是否在失巢凋亡中起作用，我们在体外诱导失巢凋亡，并对已知表达βA3/A1-晶体蛋白的星形胶质细胞进行了机制研究。Bit1 在视网膜中的表达模式与星形胶质细胞的发育时间相关。我们的数据还表明，星形胶质细胞中βA3/A1-晶体蛋白的缺失导致 Bit1 无法被运输到高尔基氏体，从而抑制失巢凋亡。这种βA3/A1-晶体蛋白的缺失还诱导胰岛素样生长因子-II 的产生，通过调节磷脂酰肌醇-3-激酶（PI3K）/AKT/mTOR 和细胞外信号调节激酶途径，增加细胞存活和生长。我们提出，βA3/A1-晶体蛋白是眼部星形胶质细胞中生死决定的新调节因子。
