Anoikis effector Bit1 negatively regulates Erk activity
Anoikis effector Bit1 negatively regulates Erk activity
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DOI：
10.1073/pnas.0711357105
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发表时间：
2008-02-05
影响因子：
11.1
通讯作者：
Ruoslahti, Erkki
中科院分区：
文献类型：
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作者：
Kairouz-Wahbe, Rania;Biliran, Hector;Ruoslahti, Erkki
Bcl-2转录抑制因子（Bit 1）是一种线粒体蛋白，其功能为肽基-tRNA水解酶，但是，当释放到细胞质中时，它会引起细胞凋亡。促凋亡功能是独特的抵消整合素介导的细胞附着。我们通过使用Cre-LoxP重组系统产生Bit 1基因的条件性KO小鼠。Bit 1基因缺失的小鼠出生时是活的，但有一些发育异常。他们开发了一个运行综合征胎盘和死亡的前2周内。培养的成纤维细胞从Bit 1-null胚胎[小鼠胚胎成纤维细胞（MEFs）]更耐细胞死亡诱导的细胞外基质（失巢凋亡）比细胞从野生型或杂合子同窝出生。来自Bit 1 KO小鼠的MEF和组织显示Erk磷酸化显著增加。在培养的细胞中敲低Bit 1表达导致Erk活化增加，并且部分敲低Erk逆转了Bit 1敲低所增加的失巢凋亡抗性。增强的Erk活化与降低的Erk磷酸酶活性相关。这些研究确立了Bit 1活性的生理意义，并开始描绘了通过Erk调节起作用的Bit 1信号通路。
Bcl-2 inhibitor of transcription (Bit1) is a mitochondrial protein that functions as a peptidyl-tRNA hydrolase, but, when released into the cytoplasm, it elicits apoptosis. The proapoptotic function is uniquely counteracted by integrin-mediated cell attachment. We generated a conditional KO mouse of the Bit1 gene by using the Cre-LoxP recombination system. Bit1-null mice were born alive but with some developmental abnormalities. They developed a runting syndrome afterbirth and died within the first 2 weeks. Cultured fibroblasts from the Bit1-null embryos [mouse embryo fibroblasts (MEFs)] were more resistant to cell death induced by loss of attachment to extracellular matrix (anoikis) than cells from the wild-type or heterozygous littermates. MEFs and tissues from Bit1 KO mice displayed a marked increase in Erk phosphorylation. Knocking down Bit1 expression in cultured cells resulted in increased Erk activation, and partially knocking down Erk reversed the increased anoikis resistance of Bit1 knockdown. The enhanced Erk activation was associated with decreased Erk phosphatase activity. These studies establish the physiological significance of Bit1 activity and begin to delineate a Bit1 signaling pathway that acts through Erk regulation.