神经元的生存能力受可逆的bad的磷酸化作用调节
【摘要】人们普遍认为B淋巴细胞瘤-2家族成员在程序性细胞死亡中起决定性作用。我们证实在大脑中动脉闭塞30 min之后的8 h，小鼠脑组织中Bad的表达异常增加。当TGF-ß1被包含一个TGF-ß1DNA的腺病毒载体正向调节时，这种异常增加近于停止了；同时，脑组织免于缺血损害。当用十字孢碱处理从新生小鼠获取的海马神经元的原代培养物以产生程序性细胞死亡，可以发现Dad水平的增加和神经原变性。此外，TGF-ß1抑制Bad表达的增加并保护细胞免于损伤。TGF-ß1的神经保护作用是通过MAPK\Erk(促分裂原活化蛋白激酶÷细胞外信号调节激酶)途径的Bad的磷酸化介导的。Bad被假定是通过结合抗程序性细胞死亡的Bcl-xl从而引起程序性细胞死亡，并与14-3-3蛋白结合。游离的Bcl-xl接着保护细胞免于损伤。问题在于是否蛋白质磷酸酶使Bad去磷酸化，从而导致了程序性细胞死亡。我们证实了蛋白质磷酸酶2C(PP2C)使Bad在所有已知磷酸位点去磷酸化。具有特殊结构性质的亲脂性复合物能显著激活PP2C并能增强培养的神经元的程序性细胞死亡损伤。因此我们认为在研究神经原程序性细胞死亡时应涉及PP2C。
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【关键字】程序性细胞死亡，生长因子，局部缺血，肿瘤基因，磷酸酶
Neuronal viability regulated by reversible phosphorylation of Bad
J. Krieglstein
Institute for Pharmacology and Toxicology, Philipps-University, Ketzerbach 63, 35032 Marburg, Germany
It is generally accepted that the members of the Bcl-2 family play a crucial role in programmed cell death (apoptosis). We could demonstrate that the expression of Bad was increased tremendously in mouse brain tissue 8 h after a 30 min occlusion of the middle cerebral artery. This increase was nearly abolished, when TGF-ß1 was upregulated in brain tissue by an adenovirus vector containing TGF-ß1 DNA and, concomitantly, the brain was protected against ischemic damage. An increase in the Bad level and neuronal degeneration was also shown when primary cultures of hippocampal neurons obtained from neonatal rats were treated with staurosporine to cause apoptosis. In addition, TGF-ß1 inhibited the increase in Bad expression and protected the cells against damage. The neuroprotective effect of TGF-ß1 seemed to be mediated by phosphorylation of Bad via the MAPK/Erk pathway. Bad is assumed to cause apoptosis by binding to the anti-apoptotic Bcl-xl and binds to 14-3-3 proteins. The free Bcl-xl protects now the cells against damage. The question arose whether protein phosphatases dephosphorylate Bad and, thereby, cause apoptosis. We demonstrated that the protein phosphatase type 2C (PP2C) dephosphorylated Bad at all phosphorylation sites known. Lipophilic compounds with special structural properties could activate PP2C markedly and increased the apoptotic damage of cultured neurons. Therefore, we suggest PP2C to be involved in neuronal apoptosis.
【Key words】 apoptosis, growth factors, ischemia, oncogene, phosphatase., 百拇医药(Josef krieblstein(德国))
, http://www.100md.com
【关键字】程序性细胞死亡，生长因子，局部缺血，肿瘤基因，磷酸酶
Neuronal viability regulated by reversible phosphorylation of Bad
J. Krieglstein
Institute for Pharmacology and Toxicology, Philipps-University, Ketzerbach 63, 35032 Marburg, Germany
It is generally accepted that the members of the Bcl-2 family play a crucial role in programmed cell death (apoptosis). We could demonstrate that the expression of Bad was increased tremendously in mouse brain tissue 8 h after a 30 min occlusion of the middle cerebral artery. This increase was nearly abolished, when TGF-ß1 was upregulated in brain tissue by an adenovirus vector containing TGF-ß1 DNA and, concomitantly, the brain was protected against ischemic damage. An increase in the Bad level and neuronal degeneration was also shown when primary cultures of hippocampal neurons obtained from neonatal rats were treated with staurosporine to cause apoptosis. In addition, TGF-ß1 inhibited the increase in Bad expression and protected the cells against damage. The neuroprotective effect of TGF-ß1 seemed to be mediated by phosphorylation of Bad via the MAPK/Erk pathway. Bad is assumed to cause apoptosis by binding to the anti-apoptotic Bcl-xl and binds to 14-3-3 proteins. The free Bcl-xl protects now the cells against damage. The question arose whether protein phosphatases dephosphorylate Bad and, thereby, cause apoptosis. We demonstrated that the protein phosphatase type 2C (PP2C) dephosphorylated Bad at all phosphorylation sites known. Lipophilic compounds with special structural properties could activate PP2C markedly and increased the apoptotic damage of cultured neurons. Therefore, we suggest PP2C to be involved in neuronal apoptosis.
【Key words】 apoptosis, growth factors, ischemia, oncogene, phosphatase., 百拇医药(Josef krieblstein(德国))