COP9 signalosome subunit 6 mediates PDGF -induced pulmonary arterial smooth muscle cells proliferation
COP9 signalosome subunit 6 mediates PDGF -induced pulmonary arterial smooth muscle cells proliferation
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COP9信号体亚基6介导PDGF诱导的肺动脉平滑肌细胞增殖
DOI：
10.1016/j.yexcr.2018.08.032
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发表时间：
2018-10-15
影响因子：
3.7
通讯作者：
Li，Manxiang
中科院分区：
文献类型：
--
作者：
Zhu，Yanting;Li，Fangwei;Li，Manxiang
哺乳动物COP 9信号体亚基6（CSN 6）的上调和随后SCF泛素连接酶底物受体β-转导重复蛋白（β-TrCP）的减少已被证明与癌细胞增殖相关。然而，目前尚不清楚CSN 6和β-TrCP是否也参与PDGF诱导的肺动脉平滑肌细胞（PASMCs）增殖。本研究旨在解决这一问题，并进一步探讨其潜在的机制。我们的研究结果表明，PDGF磷酸化Akt，刺激PASMCs增殖;而抑制PDGF受体（PDGFR）的伊马替尼阻止这些作用。PDGF进一步上调CSN 6蛋白表达，并伴有β-TrCP减少和Cdc 25 A增加。抑制PDGFR/PI 3 K/Akt信号通路可逆转PDGF诱导的这种变化和细胞增殖。预先转染CSN 6 siRNA可阻断PDGF诱导的β-TrCP下调、Cdc 25 A上调和细胞增殖。此外，MG-132预处理细胞也消除了PDGF诱导的β-TrCP减少、Cdc 25 A升高和细胞增殖。此外，通过siRNA转染预先耗尽Cdc 25 A抑制PDGF诱导的PASMCs增殖。总而言之，我们的研究表明，PDGFR/PI 3 K/Akt信号通路上调CSN 6通过增加β-TrCP的遍在蛋白化降解来减少β-TrCP，从而增加Cdc 25 A的表达，从而促进PDGF诱导的PASMC增殖。
Up-regulation of mammalian COP9 signalosome subunit 6 (CSN6) and consequent reduction of SCF ubiquitin ligase substrate receptor β-transduction repeat-containing protein (β-TrCP) have been shown to be associated with cancer cells proliferation. However, it is unclear whether CSN6 and β-TrCP are also involved in PDGF-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation. This study aims to address this issue and further explore its potential mechanisms. Our results indicated that PDGF phosphorylated Akt, stimulated PASMCs proliferation; while inhibition of PDGF receptor (PDGFR) by imatinib prevented these effects. PDGF further up-regulated CSN6 protein expression, this was accompanied with β-TrCP reduction and increase of Cdc25A. Inhibition of PDGFR/PI3K/Akt signaling pathway reversed PDGF-induced such changes and cell proliferation. Prior transfection of CSN6 siRNA blocked PDGF-induced β-TrCP down-regulation, Cdc25A up-regulation and cell proliferation. Furthermore, pre-treatment of cells with MG-132 also abolished PDGF-induced β-TrCP reduction, Cdc25A elevation and cell proliferation. In addition, pre-depletion of Cdc25A by siRNA transfection suppressed PDGF-induced PASMCs proliferation. Taken together, our study indicates that up-regulation of CSN6 by PDGFR/PI3K/Akt signaling pathway decreases β-TrCP by increasing its ubiquitinated degradation, and thereby increases the expression of Cdc25A, which promotes PDGF-induced PASMCs proliferation.