DARPP-32: from neurotransmission to cancer.
DARPP-32: from neurotransmission to cancer.
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DOI：
10.18632/oncotarget.7268
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发表时间：
2016-04-05
期刊：
影响因子：
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通讯作者：
El-Rifai W
中科院分区：
文献类型：
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作者：
Belkhiri A;Zhu S;El-Rifai W
多巴胺和cAMP调节的磷蛋白Mr 32，000（DARPP-32），也称为磷蛋白磷酸酶-1调节亚基1B（PPP 1 R1 B），最初被发现是大脑新纹状体中多巴胺活化蛋白激酶A（PKA）的底物。虽然PKA在Thr-34处的磷酸化将DARPP-32转化为蛋白磷酸酶1（PP 1）的有效抑制剂，但在Thr-75处的磷酸化将DARPP-32转化为PKA的抑制剂。通过调节DARPP-32磷酸化和调节蛋白磷酸酶和激酶活性，DARPP-32在介导由多巴胺和其他神经递质控制的生物化学、电生理和行为效应中起关键作用，以响应滥用药物和精神兴奋剂。DARPP-32及其截短亚型（t-DARPP）的表达改变，特别是在前额叶皮层中，与精神分裂症和双相情感障碍有关。此外，钙蛋白酶对DARPP-32的切割与阿尔茨海默病有关。DARPP-32在17 q12的基因组位点的扩增已经在几种癌症中描述。DARPP-32和t-DARPP在乳腺癌、前列腺癌、结肠癌和胃癌中经常在mRNA和蛋白质水平上过表达。几项研究证明了DARPP-32在癌症中的促存活、促侵袭和促血管生成功能。DARPP-32和t-DARPP的过表达还通过调节原癌信号转导途径促进胃癌和乳腺癌中的化疗药物抗性和细胞增殖。DARPP-32研究从神经传递到癌症的扩展强调了这种蛋白质在不同人类疾病中的广泛范围和意义。
Dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32), also known as phosphoprotein phosphatase-1 regulatory subunit 1B (PPP1R1B), was initially discovered as a substrate of dopamine-activated protein kinase A (PKA) in the neostriatum in the brain. While phosphorylation at Thr-34 by PKA converts DARPP-32 into a potent inhibitor of protein phosphatase 1 (PP1), phosphorylation at Thr-75 transforms DARPP-32 into an inhibitor of PKA. Through regulation of DARPP-32 phosphorylation and modulation of protein phosphatase and kinase activities, DARPP-32 plays a critical role in mediating the biochemical, electrophysiological, and behavioral effects controlled by dopamine and other neurotransmitters in response to drugs of abuse and psychostimulants. Altered expression of DARPP-32 and its truncated isoform (t-DARPP), specifically in the prefrontal cortex, has been associated with schizophrenia and bipolar disorder. Moreover, cleavage of DARPP-32 by calpain has been implicated in Alzheimer's disease. Amplification of the genomic locus of DARPP-32 at 17q12 has been described in several cancers. DARPP-32 and t-DARPP are frequently overexpressed at the mRNA and protein levels in adenocarcinomas of the breast, prostate, colon, and stomach. Several studies demonstrated the pro-survival, pro-invasion, and pro-angiogenic functions of DARPP-32 in cancer. Overexpression of DARPP-32 and t-DARPP also promotes chemotherapeutic drug resistance and cell proliferation in gastric and breast cancers through regulation of pro-oncogenic signal transduction pathways. The expansion of DARPP-32 research from neurotransmission to cancer underscores the broad scope and implication of this protein in disparate human diseases.