βA3/A1-Crystallin controls anoikis-mediated cell death in astrocytes by modulating PI3K/AKT/mTOR and ERK survival pathways through the PKD/Bit1-signaling axis.
βA3/A1-Crystallin controls anoikis-mediated cell death in astrocytes by modulating PI3K/AKT/mTOR and ERK survival pathways through the PKD/Bit1-signaling axis.
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DOI：
10.1038/cddis.2011.100
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发表时间：
2011-10-13
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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在眼睛发育过程中，细胞凋亡对于晶状体和视网膜等高度特化结构的成熟至关重要。已经描述了几种形式的细胞凋亡，包括anoikis，一种由细胞基质接触不足或不适当引发的细胞凋亡形式。当晶状体纤维中存在细胞器时，晶状体发育过程中会表达bi1（转录-1的Bcl-2抑制剂）和蛋白激酶d (PKD)，但当主动去核开始时，它们会下调表达。我们之前的研究表明，编码βA3/ a1结晶蛋白的Cryba1基因自发突变的大鼠，晶状体纤维的正常去核受到抑制。在这种突变（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-crystallin是否在anoikis中起作用，我们在体外诱导anoikis，并对已知表达βA3/A1-crystallin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具有时序相关性。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体，从而抑制疾病的发生。这种βA3/ a1 -晶体蛋白的缺失也诱导胰岛素样生长因子- ii，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 -晶体蛋白是眼星形胶质细胞生死决定的一种新的调节因子。
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.
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DOI：
10.1073/pnas.0711357105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Kairouz-Wahbe, Rania;Biliran, Hector;Ruoslahti, Erkki
通讯作者：
Ruoslahti, Erkki
影响因子：
64.5
作者：
Jan, YW;Matter, M;Ruoslahti, E
通讯作者：
Ruoslahti, E
影响因子：
7.8
作者：
Bassnett, S;Mataic, D
通讯作者：
Mataic, D
影响因子：
16.2
作者：
MARTINOU, JC;DUBOISDAUPHIN, M;HUARTE, J
通讯作者：
HUARTE, J
影响因子：
3.3
作者：
Gehlbach, P;Hose, S;Sinha, D
通讯作者：
Sinha, D