COP9 signalosome subunit 6 mediates PDGF -induced pulmonary arterial smooth muscle cells proliferation

Yanting Zhu, Fangwei Li, Wenhua Shi, Cui Zhai, Jian Wang, Xin Yan, Qingting Wang, Qianqian Zhang, Lan Yang, Li Gao, Manxiang Li

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)379-388
Number of pages10
JournalExperimental cell research
Volume371
Issue number2
DOIs
StatePublished - Oct 15 2018

Keywords

  • COP9 signalosome subunit 6 (CSN6)
  • Cdc25A
  • Proliferation
  • Pulmonary arterial smooth muscle cells
  • β-transduction repeat-containing protein (β-TrCP)

ASJC Scopus subject areas

  • Cell Biology

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