Inhibition of phosphatidylinostol 3-kinase uncouples H2O 2-induced senescent phenotype and cell cycle arrest in normal human diploid fibroblasts

Yong Wang, Aimin Meng, Daohong Zhou

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Exposure of WI38 human diploid fibroblasts (HDFs) to hydrogen peroxide (H2O2) induced premature senescence. The senescent HDFs were permanently arrested and exhibited a senescent phenotype including enlarged and flattened cell morphology and increased senescence-associated β-galactosidase (SA-β-gal) activity. The induction of HDF senescence was associated with an activation of p53, increased expression of p21 Cip1/WAF1, and hypophosphorylation of retinoblastoma protein (Rb), while no changes in the expression of p16Ink4a, p27Kip1, and p14Arf were observed. Exposure of WI38 cells to H 2O2 also selectively activated phosphatidylinostol 3-kinase (PI3 kinase) and mitogen-activated protein kinase (MAPK) kinase (MEK), while no changes in p38 MAPK and Jun kinase (JNK) activities were observed. Selective inhibition of PI3 kinase activity with LY294002 abrogated H 2O2-induced cell enlargement and flattened morphology and significantly attenuated the increase in SA-β-gal activity, but did not affect H2O2-induced cell cycle arrest. In contrast, selective inhibition of MEK and p38 MAPK with PD98059 and SB203580, respectively, produced no significant effect on H2O 2-induced senescent phenotype and cell cycle arrest. These findings demonstrate that expression of the senescent phenotype can be uncoupled from cell cycle arrest in prematurely senescent cells induced by H2O 2 and does not contribute to the maintenance of permanent cell cycle arrest.

Original languageEnglish (US)
Pages (from-to)188-196
Number of pages9
JournalExperimental Cell Research
Volume298
Issue number1
DOIs
StatePublished - Aug 1 2004
Externally publishedYes

Keywords

  • Human diploid fibroblasts
  • Hydrogen peroxide
  • PI3 kinase
  • Senescence

ASJC Scopus subject areas

  • Cell Biology

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