Identification of DBC1 as a transcriptional repressor for BRCA1.
BACKGROUND
DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumour-suppressor gene cloned from a heterozygously deleted region in breast cancer specimens. Caspase-dependent processing of DBC1 promotes apoptosis, and depletion of endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1. Hereditary breast and ovarian cancer susceptibility gene product BRCA1, by binding to the promoter region of SIRT1, is a positive regulator of SIRT1 expression.


METHODS
A physical interaction between DBC1 and BRCA1 was investigated both in vivo and in vitro. To determine the pathophysiological significance of DBC1, its role as a transcriptional factor was studied.


RESULTS
We found a physical interaction between the amino terminus of DBC1 and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous DBC1 and BRCA1 form a complex in the nucleus of intact cells, which is exported to the cytoplasm during ultraviolet-induced apoptosis. We also showed that the expression of DBC1 represses the transcriptional activation function of BRCT by a transient expression assay. The expression of DBC1 also inhibits the transactivation of the SIRT1 promoter mediated by full-length BRCA1.


CONCLUSIONS
These results revealed that DBC1 may modulate the cellular functions of BRCA1 and have important implications in the understanding of carcinogenesis in breast tissue.
Hiraike
H
H
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan. osamu.hiraike@gmail.com
Wada-Hiraike
O
O
Nakagawa
S
S
Koyama
S
S
Miyamoto
Y
Y
Sone
K
K
Tanikawa
M
M
Tsuruga
T
T
Nagasaka
K
K
Matsumoto
Y
Y
Oda
K
K
Shoji
K
K
Fukuhara
H
H
Saji
S
S
Nakagawa
K
K
Kato
S
S
Yano
T
T
Taketani
Y
Y
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics; D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology; D056564:Sirtuin 1 / Q000235:genetics; D014018:Tissue Distribution; D015533:Transcriptional Activation / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C527450:CCAR2 protein, human; D012097:Repressor Proteins; C447939:SIRT1 protein, human; D056564:Sirtuin 1