DBC1 functions as a tumor suppressor by regulating p53 stability.
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.
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.
Bo
B
Qin
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Katherine
K
Minter-Dykhouse
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Jia
J
Yu
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Jun
J
Zhang
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
Tongzheng
T
Liu
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
Haoxing
H
Zhang
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
SeungBaek
S
Lee
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
JungJin
J
Kim
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Liewei
L
Wang
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: lou.zhenkun@mayo.edu.
Zhenkun
Z
Lou
D000818:Animals; D063646:Carcinogenesis; D018797:Cell Cycle Proteins; D002460:Cell Line; D049109:Cell Proliferation; D018572:Disease-Free Survival; D006801:Humans; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C491992:BRINP1 protein, mouse; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex; D056564:Sirtuin 1