DBC1 functions as a tumor suppressor by regulating p53 stability

Cell Rep. 2015 Mar 3;10(8):1324-34. doi: 10.1016/j.celrep.2015.01.066. Epub 2015 Feb 26.

Abstract

DBC1 (deleted in breast cancer 1), also known as CCAR2 or KIAA1967, is an important negative regulator of SIRT1 and cellular stress response. Although the Dbc1 gene localizes at a region that is homozygously deleted in breast cancer, its role in tumorigenesis remains unclear. It has been suggested to be either a tumor suppressor or an oncogene. Therefore, the function of DBC1 in cancer needs to be further explored. Here, we report that Dbc1 knockout mice are tumor prone, suggesting that DBC1 functions as a tumor suppressor in vivo. Our data suggest that the increased tumor incidence in Dbc1 knockout mice is independent of Sirt1. Instead, we found that DBC1 loss results in less p53 protein in vitro and in vivo. DBC1 directly binds p53 and stabilizes it through competition with MDM2. These studies reveal that DBC1 plays an important role in tumor suppression through p53 regulation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinogenesis
  • Cell Cycle Proteins
  • Cell Line
  • Cell Proliferation
  • Disease-Free Survival
  • Humans
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Stability
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitination

Substances

  • BRINP1 protein, mouse
  • Cell Cycle Proteins
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • Proteasome Endopeptidase Complex
  • Sirtuin 1