Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function.
Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function.
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DOI：
10.1126/sciadv.ade1694
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发表时间：
2023-01-06
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
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脊髓和延髓肌萎缩是由雄激素受体（AR）中的聚谷氨酰胺（polyQ）扩增引起的，产生可能涉及磷酸化的功能获得性毒性。使用细胞和动物模型，我们研究了哪些激酶和磷酸酶靶向polyQ扩展的AR，polyQ扩展是否改变AR磷酸化，以及这如何导致神经退行性变。质谱分析表明，polyQ扩增保留了天然磷酸化，并增加了控制AR稳定性和反式激活的保守位点的磷酸化。在小分子筛选中，我们发现CDC 25/CDK 2信号可以增强AR磷酸化，而钙敏感磷酸酶钙调神经磷酸酶具有相反的作用。这些激酶和磷酸酶的药理学和遗传操作修饰了细胞、果蝇和小鼠中polyQ扩增的AR功能和毒性。CDK 2的消融减少了脑干中的AR磷酸化，并恢复了Myc和其他参与DNA损伤、衰老和凋亡的基因的表达，表明细胞周期调节激酶在SBMA脆弱的有丝分裂后细胞中发挥的作用不仅仅是旁观者。CDC 25/CDK 2和钙调磷酸酶修饰SBMA中polyQ扩增的AR磷酸化、反式激活和毒性。
Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR function and toxicity in cells, flies, and mice. Ablation of CDK2 reduced AR phosphorylation in the brainstem and restored expression of Myc and other genes involved in DNA damage, senescence, and apoptosis, indicating that the cell cycle–regulated kinase plays more than a bystander role in SBMA-vulnerable postmitotic cells. CDC25/CDK2 and calcineurin modify polyQ-expanded AR phosphorylation, transactivation, and toxicity in SBMA.
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DOI：
10.1124/jpet.103.059477
发表时间：
2004-04-01
影响因子：
3.5
作者：
Han, YS;Shen, HM;Pan, SS
通讯作者：
Pan, SS
DOI：
10.1523/jneurosci.1064-09.2009
发表时间：
2009-10-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Abdul HM;Sama MA;Furman JL;Mathis DM;Beckett TL;Weidner AM;Patel ES;Baig I;Murphy MP;LeVine H 3rd;Kraner SD;Norris CM
通讯作者：
Norris CM
影响因子：
3.3
作者：
DESAI, D;GU, Y;MORGAN, DO
通讯作者：
MORGAN, DO
影响因子：
14.9
作者：
Altenhoff AM;Train CM;Gilbert KJ;Mediratta I;Mendes de Farias T;Moi D;Nevers Y;Radoykova HS;Rossier V;Warwick Vesztrocy A;Glover NM;Dessimoz C
通讯作者：
Dessimoz C
影响因子：
5.8
作者：
ENAN, E;MATSUMURA, F
通讯作者：
MATSUMURA, F