DBC1 functions as a tumor suppressor by regulating p53 stability

Bo Qin; Katherine Minter-Dykhouse; Jia Yu; Jun Zhang; Tongzheng Liu; Haoxing Zhang; SeungBaek Lee; JungJin Kim; Liewei Wang; Zhenkun Lou

doi:10.1016/j.celrep.2015.01.066

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.

Authors

Bo Qin¹, Katherine Minter-Dykhouse², Jia Yu², Jun Zhang³, Tongzheng Liu⁴, Haoxing Zhang⁴, SeungBaek Lee⁴, JungJin Kim⁴, Liewei Wang², Zhenkun Lou⁵

Affiliations

¹ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, China; Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
² Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
³ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
⁴ Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
⁵ Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: lou.zhenkun@mayo.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding