Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease
Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease
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常染色体显性多囊肾病中 cAMP-PKA 信号激活 P-TEFb
DOI：
10.1126/sciadv.aaw3593
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发表时间：
2019-06-01
期刊：
影响因子：
13.6
通讯作者：
Chen, Yupeng
中科院分区：
文献类型：
--
作者：
Sun, Yongzhan;Liu, Zhiheng;Chen, Yupeng
正性转录延伸因子b（P - TEFb）作为转录延伸的核心调节因子发挥作用。P - TEFb的激活是通过其从无转录活性的P - TEFb/HEXIM1/7SK小核核糖核蛋白复合物中解离而发生的。然而，信号调节的P - TEFb激活机制及其在人类疾病中的作用在很大程度上仍然未知。在此，我们证明环磷酸腺苷 - 蛋白激酶A（cAMP - PKA）信号通路通过蛋白激酶A介导的HEXIM1的丝氨酸 - 158位点磷酸化破坏无活性的P - TEFb/HEXIM1/7SK小核核糖核蛋白复合物。环磷酸腺苷通路在常染色体显性多囊肾病（ADPKD）的发展中起核心作用，并且我们表明P - TEFb在小鼠和人类ADPKD肾脏中过度激活。P - TEFb的基因激活促进斑马鱼ADPKD模型中的囊肿形成，而P - TEFb的药物抑制通过抑制ADPKD小鼠中的病理基因表达程序减轻囊肿发展。因此，我们的研究阐明了cAMP - PKA信号通路激活P - TEFb促进ADPKD中囊肿发生的一种机制。
P-TEFb activation by cAMP-PKA signaling promotes cystogenic gene transcription elongation and disease progression in ADPKD. Positive transcription elongation factor b (P-TEFb) functions as a central regulator of transcription elongation. Activation of P-TEFb occurs through its dissociation from the transcriptionally inactive P-TEFb/HEXIM1/7SK snRNP complex. However, the mechanisms of signal-regulated P-TEFb activation and its roles in human diseases remain largely unknown. Here, we demonstrate that cAMP-PKA signaling disrupts the inactive P-TEFb/HEXIM1/7SK snRNP complex by PKA-mediated phosphorylation of HEXIM1 at serine-158. The cAMP pathway plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD), and we show that P-TEFb is hyperactivated in mouse and human ADPKD kidneys. Genetic activation of P-TEFb promotes cyst formation in a zebrafish ADPKD model, while pharmacological inhibition of P-TEFb attenuates cyst development by suppressing the pathological gene expression program in ADPKD mice. Our study therefore elucidates a mechanism by which P-TEFb activation by cAMP-PKA signaling promotes cystogenesis in ADPKD.