The PTEN/PI3K/Akt signaling pathway mediates HMGB1-induced cell proliferation by regulating the NF-κB/cyclin D1 pathway in mouse mesangial cells

Am J Physiol Cell Physiol. 2014 Jun 15;306(12):C1119-28. doi: 10.1152/ajpcell.00385.2013. Epub 2014 Apr 23.

Abstract

Our previous experiment confirmed that high-mobility group box chromosomal protein 1 (HMGB1) was involved in the pathogenesis of Lupus nephritis (LN) by upregulating the proliferation of the mouse mesangial cell line (MMC) through the cyclin D1/CDK4/p16 system, but the precise mechanism is still unknown. Therefore, in the present study, we demonstrated that HMGB1 induced the proliferation of MMC cells in a time- and concentration-dependent manner, downregulated phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression, increased the level of Akt serine 473 phosphorylation, and induced p65 subunit nuclear translocation. The overexpression of PTEN prevented the upregulation of HMGB1-induced proliferation by blocking the activation of Akt. The knockdown of Akt by siRNA technology and blocking the nuclear factor-κB (NF-κB) pathway using pyrrolidine dithiocarbamate (PDTC) and SN50, inhibitors of NF-κB, both attenuated the HMGB1-induced proliferation by counteracting the activation of the cyclin D1. In addition, while sh-Akt partly blocked the nuclear translocation of the p65 subunit, PDTC did not affect the activation of the Akt induced by HMGB1 in MMC cells. These findings indicate that HMGB1 induced the proliferation of MMC cells by activating the PTEN/phosphoinositide-3-kinase (PI3K)/Akt/NF-κB signaling pathway.

Keywords: Akt; HMGB1; NF-κB; PTEN; cell proliferation; mouse mesangial cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cyclin D1 / genetics*
  • Cyclin D1 / metabolism
  • Gene Knockdown Techniques
  • HMGB1 Protein / genetics*
  • HMGB1 Protein / metabolism
  • Lupus Nephritis / genetics*
  • Lupus Nephritis / metabolism
  • Lupus Nephritis / pathology
  • Mesangial Cells / metabolism*
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Oncogene Protein v-akt / genetics
  • Oncogene Protein v-akt / metabolism
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphorylation
  • Signal Transduction / genetics

Substances

  • HMGB1 Protein
  • HMGB1 protein, mouse
  • NF-kappa B
  • Cyclin D1
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse