p27 Kip1 represses the Pitx2-mediated expression of p21 Cip1 and regulates DNA replication during cell cycle progression

Oncogene. 2017 Jan 19;36(3):350-361. doi: 10.1038/onc.2016.200. Epub 2016 Jun 6.

Abstract

The tumor suppressor p21 regulates cell cycle progression and peaks at mid/late G1. However, the mechanisms regulating its expression during cell cycle are poorly understood. We found that embryonic fibroblasts from p27 null mice at early passages progress slowly through the cell cycle. These cells present an elevated basal expression of p21 suggesting that p27 participates to its repression. Mechanistically, we found that p27 represses the expression of Pitx2 (an activator of p21 expression) by associating with the ASE-regulatory region of this gene together with an E2F4 repressive complex. Furthermore, we found that Pitx2 binds to the p21 promoter and induces its transcription. Finally, silencing Pitx2 or p21 in proliferating cells accelerates DNA replication and cell cycle progression. Collectively, these results demonstrate an unprecedented connection between p27, Pitx2 and p21 relevant for the regulation of cell cycle progression and cancer and for understanding human pathologies associated with p27 germline mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics*
  • DNA / genetics*
  • DNA Replication*
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism
  • Gene Expression Profiling
  • Gene Knockout Techniques
  • HEK293 Cells
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Promoter Regions, Genetic
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Cdkn1a protein, mouse
  • Cdkn1b protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Homeodomain Proteins
  • Transcription Factors
  • Cyclin-Dependent Kinase Inhibitor p27
  • homeobox protein PITX2
  • DNA