Laboratory of Molecular Biology, NINDS, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 2013 Jul 12;288(28):20151-61. doi: 10.1074/jbc.M113.470583. Epub 2013 Jun 3.
Neonatal brains develop through a program that eliminates about half of the neurons. During this period, neurons depend on neurotrophins for their survival. Recently, we reported that, at the conclusion of the naturally occurring death period, neurons become neurotrophin-independent and, further, that this developmental switch is achieved by the emergence of a second survival pathway mediated by signal transducer and activator of transcription 3 (STAT3). Here I show that calcineurin plays a key role in controlling the developmental switch in mouse hippocampal neurons. Calcineurin promotes the degradation of STAT3 via the ubiquitin-proteasome pathway. Inhibition of calcineurin acutely increases total levels of STAT3 as well as its activated forms, resulting in decreased levels of the tumor suppressor p53 and its proapoptotic target, Bax. In vivo and in vitro, calcineurin regulates levels of STAT3 and neurotrophin dependence. TMF/ARA 160 (TATA element modulatory factor/androgen receptor co-activator 160), the key mediator of STAT3 ubiquitination, is required for calcineurin-dependent STAT3 degradation. Thus, these results show that the ubiquitin-proteasome pathway controls the critical developmental switch of neurotrophin dependence in the newborn hippocampus.
新生儿大脑通过一个程序性细胞死亡过程发育，在此过程中约有一半神经元会凋亡。在此期间，神经元依赖神经营养因子存活。最近，我们报道称，在自然发生的死亡期结束时，神经元不再依赖神经营养因子，并且这种发育转换是通过由信号转导和转录激活因子 3（STAT3）介导的第二种存活途径的出现来实现的。在这里，我表明钙调神经磷酸酶在控制小鼠海马神经元发育转换中起关键作用。钙调神经磷酸酶通过泛素-蛋白酶体途径促进 STAT3 的降解。钙调神经磷酸酶的抑制作用会导致 STAT3 的总水平及其激活形式增加，从而降低肿瘤抑制因子 p53 及其促凋亡靶标 Bax 的水平。在体内和体外，钙调神经磷酸酶调节 STAT3 的水平和神经营养因子的依赖性。TATA 元件调节因子/雄激素受体共激活因子 160（TMF/ARA 160）是 STAT3 泛素化的关键介质，是钙调神经磷酸酶依赖性 STAT3 降解所必需的。因此，这些结果表明，泛素-蛋白酶体途径控制着新生海马体中神经营养因子依赖性的关键发育转换。
