...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Survival function of ERK1/2 as lL-3-activated, staurosporine-resistant BcI2 kinases
【24h】

Survival function of ERK1/2 as lL-3-activated, staurosporine-resistant BcI2 kinases

机译：ERK1 / 2作为lL-3激活，耐星形孢菌素的BclI2激酶的生存功能

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Bcl2 phosphorylation at Ser-70 may be required forthe full and potent suppression of apoptosis in IL-3-dependent myeloid cells and can result from agonist activation of mitochondrial protein kinase C (PKC). Paradoxically, expression of exogenous BcI2 can protect parental cells from apoptosis induced by the potent PKC inhibitor, staurosporine (stauro). High concentrations of stauro of up to 1 pM only partially inhibit lL-3-stimulated Bd2 phosphorylation but completely block PKC-mediated BcI2 phosphorylation in vbo. These data indicate a role for a Stauro-resistant BcI2 kinase (SRK). We show that aurintricar- boxylic acid (ATA), a nonpeptide activator of cellular MEK/mitogen- activat6d protein kinase (MAPK) kinase, can induce Ser-70 phosphor- ylation of Bcl2 and support survival of cells expressing wild-type but not the phosphorylation-incompetent S70A mutant Bcl2. A role for a MEK/MAPK as a responsible SRK was implicated because the highly specific MEK/MAPK inhibitor, PD980S9, also can only partially inhibit IL3-induced Bcl2 phosphorylation, whereas the combination of PD98059 and Stauro completely blocks phosphorylation and syner- gistically enhances apoptosis. P44MAPK/eXtracellular signal-regu- lated kinase 1 (ERK1) and P42 MAPK/ERKZ are activated by IL-3, colocalize with mitochondrial BcI2, and can directly phosphorylate Bcl2 on Ser-70 in a stauro-resistant manner both in the and in vivo. These findings suggest a role for the ERK1/2 kinases as SRKs. Thus, the SRKs can serve to functionally link the lL-3-stimulated prolifera- tive and survival signaling pathways and, in a novel capacity, may explain how Bcl2 can suppress stauro-induced apoptosis. In addition, although the mechanism of regulation of BcI2 by phosphorylation is not yet clear, our results indicate that phosphorylation may function- ally st8bilize the BcI2-Bax heterodimerization.
机译：完全和有效抑制IL-3依赖性髓样细胞凋亡可能需要Ser-70处的Bcl2磷酸化，并且可能是由于线粒体蛋白激酶C（PKC）的激动剂激活所致。矛盾的是，外源性Bcl 2的表达可以保护亲代细胞免受有效的PKC抑制剂星形孢菌素（staurosporine，stauro）诱导的凋亡。高达1 pM的高浓度stauro仅部分抑制lL-3刺激的Bd2磷酸化，但完全阻断vbo中PKC介导的BcI2磷酸化。这些数据表明耐Stauro BcI2激酶（SRK）的作用。我们显示，金黄色羧酸（ATA）是细胞MEK /有丝分裂原活化蛋白激酶（MAPK）激酶的非肽激活剂，可以诱导Bcl2的Ser-70磷酸化并支持表达野生型但未表达的细胞的存活磷酸化能力不足的S70A突变体Bcl2。暗示了MEK / MAPK作为负责任SRK的作用，因为高度特异性的MEK / MAPK抑制剂PD980S9也只能部分抑制IL3诱导的Bcl2磷酸化，而PD98059和Stauro的组合完全阻断了磷酸化并协同增强细胞凋亡。 P44MAPK /细胞外信号调节激酶1（ERK1）和P42 MAPK / ERKZ被IL-3激活，与线粒体BcI2共定位，并且可以以抗星形胶质化的方式直接磷酸化Ser-70上的Bcl2。体内。这些发现暗示了ERK1 / 2激酶作为SRK的作用。因此，SRKs可以起到功能性连接lL-3刺激的增殖和生存信号通路的作用，并以一种新颖的方式解释了Bcl2如何抑制星形胶质细胞诱导的凋亡。此外，尽管尚不清楚通过磷酸化调节BcI2的机制，但我们的结果表明，磷酸化可能在功能上稳定了BcI2-Bax异二聚体。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号