The metastasis-associated gene Prl-3 is a p53 target involved in cell-cycle regulation

Mol Cell. 2008 May 9;30(3):303-14. doi: 10.1016/j.molcel.2008.04.002.

Abstract

The p53 tumor suppressor restricts tumorigenesis through the transcriptional activation of target genes involved in cell-cycle arrest and apoptosis. Here, we identify Prl-3 (phosphatase of regenerating liver-3) as a p53-inducible gene. Whereas previous studies implicated Prl-3 in metastasis because of its overexpression in metastatic human colorectal cancer and its ability to promote invasiveness and motility, we demonstrate here that Prl-3 is an important cell-cycle regulator. Consistent with a role in DNA damage-induced cell-cycle arrest, Prl-3 overexpression induces G(1) arrest downstream of p53 by triggering a PI3K-Akt-activated negative feedback loop. Surprisingly, attenuation of Prl-3 expression also elicits an arrest response, suggesting that basal level Prl-3 expression is pivotal for normal cell-cycle progression. Our findings highlight key dose-dependent functions of Prl-3 in both positive and negative regulation of cell-cycle progression and provide insight into Prl-3's role in cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / physiology*
  • Cells, Cultured
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression Regulation
  • Humans
  • Immediate-Early Proteins / genetics*
  • Immediate-Early Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Neoplasm Invasiveness / genetics
  • Neoplasm Metastasis / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Tyrosine Phosphatases / genetics*
  • Protein Tyrosine Phosphatases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Signal Transduction / physiology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Immediate-Early Proteins
  • Ptp4a3 protein, mouse
  • Tumor Suppressor Protein p53
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Tyrosine Phosphatases