Role of p21 in SP600125-induced cell cycle arrest, endoreduplication, and apoptosis

Cell Mol Life Sci. 2011 Oct;68(19):3249-60. doi: 10.1007/s00018-011-0626-5. Epub 2011 Feb 11.

Abstract

The anti-cancer effect of the c-Jun N-terminal kinase (JNK) inhibitor SP600125 has been well evaluated in human cancer cells. However the role of p21 in SP600125-mediated G(2)/M distribution is not fully understood. Our results showed that the transcriptional activation of p21 by SP600125 is mediated through the proximal regions of multiple Sp1 sites in the p21 promoter following ERK-dependent phosphorylation of Sp1. In this process, p21 induces endoreduplication through the inhibition of cyclin E/Cdk2 activity at 24 h but does not directly regulate cyclin B1/Cdc2 activity. Furthermore, SP600125 induces the phosphorylation of p21 at Thr 145 through the PI3K/Akt pathway. Akt-mediated phosphorylation of p21 and protection of apoptosis are completely abolished by inhibitors of PI3K and Akt. In summary using time points, we identified the dual functions of p21 as an inhibitor of cell-cycle progression at 24 h and as an anti-apoptotic factor at 48 h.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracenes / pharmacology*
  • Apoptosis / drug effects*
  • Cell Cycle / drug effects*
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology*
  • G2 Phase / drug effects
  • G2 Phase / physiology
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • U937 Cells

Substances

  • Anthracenes
  • CDKN1A protein, human
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p21
  • pyrazolanthrone
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2