CDC25B induces cellular senescence and correlates with tumor suppression in a p53-dependent manner

J Biol Chem. 2021 Jan-Jun:296:100564. doi: 10.1016/j.jbc.2021.100564. Epub 2021 Mar 18.

Abstract

The phosphatase cell division cycle 25B (Cdc25B) regulates cell cycle progression. Increased Cdc25B levels are often detected in cancer cell lines and human cancers and have been implicated in contributing to tumor growth, potentially by providing cancer cells with the ability to bypass checkpoint controls. However, the specific mechanism by which increased Cdc25B impacts tumor progression is not clear. Here we analyzed The Cancer Genome Atlas (TCGA) database and found that patients with high CDC25B expression had the expected poor survival. However, we also found that high CDC25B expression had a p53-dependent tumor suppressive effect in lung cancer and possibly several other cancer types. Looking in more detail at the tumor suppressive function of Cdc25B, we found that increased Cdc25B expression caused inhibition of cell growth in human normal fibroblasts. This effect was not due to alteration of specific cell cycle stage or inhibition of apoptosis, nor by induction of the DNA damage response. Instead, increased CDC25B expression led cells into senescence. We also found that p53 was required to induce senescence, which might explain the p53-dependent tumor suppressive function of Cdc25B. Mechanistically, we found that the Cdc25B phosphatase activity was required to induce senescence. Further analysis also found that Cdc25B stabilized p53 through binding and dephosphorylating p53. Together, this study identified a tumor-suppressive function of Cdc25B that is mediated through a p53-dependent senescence pathway.

Keywords: CDC25B; p53; phosphatase; senescence; tumor suppression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle
  • Cell Line, Tumor
  • Cellular Senescence*
  • DNA Damage
  • Humans
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53