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

Exp Cell Res. 2018 Oct 15;371(2):379-388. doi: 10.1016/j.yexcr.2018.08.032. Epub 2018 Sep 1.

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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COP9 Signalosome Complex / antagonists & inhibitors
  • COP9 Signalosome Complex / genetics*
  • COP9 Signalosome Complex / metabolism
  • Cell Proliferation / drug effects
  • Cysteine Proteinase Inhibitors / pharmacology
  • Gene Expression Regulation
  • Imatinib Mesylate / pharmacology
  • Leupeptins / pharmacology
  • Male
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Platelet-Derived Growth Factor / genetics*
  • Platelet-Derived Growth Factor / metabolism
  • Platelet-Derived Growth Factor / pharmacology
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pulmonary Artery / cytology
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
  • Receptors, Platelet-Derived Growth Factor / genetics*
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Signal Transduction
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / metabolism
  • cdc25 Phosphatases / genetics
  • cdc25 Phosphatases / metabolism

Substances

  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Platelet-Derived Growth Factor
  • RNA, Small Interfering
  • beta-Transducin Repeat-Containing Proteins
  • Imatinib Mesylate
  • Phosphatidylinositol 3-Kinases
  • Receptors, Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-akt
  • Cdc25a protein, rat
  • cdc25 Phosphatases
  • COP9 Signalosome Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde