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

Journal Article · Mon Oct 15 04:00:00 EDT 2018 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2018.08.032· OSTI ID:23082570

Zhu, Yanting; Li, Fangwei; Shi, Wenhua; Zhai, Cui; Wang, Jian ^[1]; others, and

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1. Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061 (China)

Highlights: • CSN6 is up-regulated in PASMCs stimulated with PDGF. • Activated PDGFR/PI3K/Akt signaling pathway up-regulats CSN6 in PDGF-induced PASMCs. • CSN6 increases β-TrCP ubiquitinated degradation and thereby up-regulates Cdc25A. • Up-regulation of Cdc25A promotes PDGF-induced PASMCs proliferation. 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.

• OSTI ID: 23082570
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 2 Vol. 371; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CELL PROLIFERATION
LIGASES
MUSCLES
NEOPLASMS