AKT and CDK5/p35 mediate brain-derived neurotrophic factor induction of DARPP-32 in medium size spiny neurons in vitro

被引:50
作者
Bogush, Alexey
Pedrini, Steve
Pelta-Heller, Joshua
Chan, Tung
Yang, Qian
Mao, Zixu
Sluzas, Emily
Gieringer, Tracy
Ehrlich, Michelle E.
机构
[1] Thomas Jefferson Univ, Dept Neurol, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Farber Inst Neurosci, Philadelphia, PA 19107 USA
[3] Thomas Jefferson Univ, Ctr Translat Res, Philadelphia, PA 19107 USA
[4] Emory Univ, Sch Med, Dept Pharmacol & Neurol, Atlanta, GA 30322 USA
关键词
D O I
10.1074/jbc.M606508200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mature striatal medium size spiny neurons express the dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa (DARPP-32), but little is known about the mechanisms regulating its levels or the specification of fully differentiated neuronal subtypes. Cell extrinsic molecules that increase DARPP-32 mRNA and/or protein levels include brain-derived neurotrophic factor (BDNF), retinoic acid, and estrogen. DARPP-32 induction by BDNF in vitro requires phosphatiaylinositide 3-kinase (PI3K), but inhibition of phosphorylation of protein kinase B/Akt does not entirely abolish expression of DARPP-32. Moreover, the requirement for Akt has not been established. Using pharmacologic inhibitors of PI3K, Akt, and cyclin-dependent kinase 5 (cdk5) and constitutively active and dominant negative PI3K, Akt, cdk5, and p35 viruses in cultured striatal neurons, we measured BDNF-induced levels of DARPP-32 protein and/or mRNA. We demonstrated that both the PI3K/Akt/mammalian target of rapamycin and the cdk5/p35 signal transduction pathways contribute to the induction of DARPP-32 protein levels by BDNF and that the effects are on both the transcriptional and translational levels. It also appears that PI3K is upstream of cdk5/p35, and its activation can lead to an increase in p35 protein levels. These data support the presence of multiple signal transduction pathways mediating expression of DARPP-32 in vitro, including a novel, important pathway via by which PI3K regulates the contribution of cdk5/p35.
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收藏
页码:7352 / 7359
页数:8
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