Spinophilin Acts as a Tumor Suppressor by Regulating Rb Phosphorylation

Cell Cycle. 2011 Aug 15;10(16):2751-62. doi: 10.4161/cc.10.16.16422. Epub 2011 Aug 15.

Abstract

The scaffold protein Spinophilin (SPN) is a regulatory subunit of phosphatase1a located at 17q21.33. This region is frequently associated with microsatellite instability and LOH containing a relatively high density of known tumor suppressor genes, including BRCA1. Several linkage studies have suggested the existence of an unknown tumor suppressor gene distal to BRCA1. Spn may be this gene, but the mechanism through which this gene makes its contribution to cancer has not been described. In this study, we aimed to determine how loss of Spn may contribute to tumorigenesis. We explored the contribution of SPN to PP1a-mediated Rb regulation. We found that the loss of Spn downregulated PPP1CA and PP1a activity, resulting in a high level of phosphorylated Rb and increased ARF and p53 activity. However, in the absence of p53, reduced levels of SPN enhanced the tumorigenic potential of the cells. Furthermore, the ectopic expression of SPN in human tumor cells greatly reduced cell growth. Taken together, our results demonstrate that the loss of Spn induces a proliferative response by increasing Rb phosphorylation, which, in turn, activates p53, thereby neutralizing the proliferative response. We suggest that Spn may be the tumor suppressor gene located at 17q21.33 acting through Rb regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factor 1 / metabolism
  • Animals
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • Doxorubicin / pharmacology
  • Etoposide / pharmacology
  • Hydrogen Peroxide / pharmacology
  • Methylcholanthrene / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Phosphorylation
  • Protein Phosphatase 1 / genetics
  • Protein Phosphatase 1 / metabolism
  • Retinoblastoma Protein / metabolism*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • neurabin
  • Methylcholanthrene
  • Etoposide
  • Doxorubicin
  • Hydrogen Peroxide
  • PPP1CA protein, mouse
  • Protein Phosphatase 1
  • ADP-Ribosylation Factor 1