CCAR2 cell cycle and apoptosis regulator 2

2011-07-01   Jian Yuan , Zhenkun Lou 

Division of Oncology Research, Mayo Clinic, Rochester, MN 55902, USA

Identity

HGNC
LOCATION
8p21.3
LOCUSID
ALIAS
DBC-1,DBC1,KIAA1967,NET35,p30
FUSION GENES

DNA/RNA

Atlas Image
Adapted from http://genome.ucsc.edu.

Description

This gene can be found on chromosome 8 at location 22462539-22477984.

Transcription

The DNA sequence contains 21 exons and the transcript length is 4012 bps translated to a 923 residues protein.

Proteins

Atlas Image

Description

Human KIAA1967/p30 DBC encodes a 923 amino acids protein with a leucine zipper motif, a Nudix domain, an EF hand motif and a coiled coil domain.

Expression

KIAA1967/p30 DBC is widely expressed in multiple tissues.

Localisation

p30 DBC has a nuclear localization motif and localizes in the nucleus.

Function

p30 DBC is an endogenous inhibitor of the class III protein deacetylase SIRT1. p30 DBC directly interacts with the catalytic domain of SIRT1 and inhibits the deacetylase activity of SIRT1. In doing so, p30 DBC promotes the acetylation of SIRT1 substrates such as p53 and FOXO3 following cellular stress in several cancer cell lines and inhibits SIRT1-dependent cell survival.
p30 DBC inhibits the activity of SUV39H1 methyltransferase and regulate heterochromatin formation via its inhibitory effect toward both SIRT1 and SUV39H1.
p30 DBC contains the Nudix hydrolase (MutT) domain, which is predicted to bind nucleoside diphosphate sugars and nicotinamide adenine dinucleotide (NAD), a co-substrate for SIRT1 enzyme. However, the Nudix domain of p30 DBC is predicted to be catalytically inactive.
In response to apoptosis-inducing signals, such as exposure to TNFalpha, etoposide or staurosporine, p30 DBC is cleaved into C-terminal p120 and p66 fragments in a caspase-dependent manner. The C-terminal fragment then relocalizes from nucleus to cytosol and mitochondria, and sensitizes cells to apoptotic stimuli. These findings suggest that p30 DBC promotes apoptosis through a positive feedback mechanism, which might suppress tumorigenesis by facilitating cell death in response to cellular stresses.
p30 DBC was found to act as a transcriptional coactivator of retinoic acid receptor alpha (RARalpha). The induction of RARalpha target genes such as Sox9 and HoxA1 gene in response to retinoic acid requires p30 DBC in MCF-7 breast cancer cells. This transcriptional activity of p30 DBC is not affected by SIRT1 inhibitor nicotinamide, suggesting that at least this transcriptional regulation function of p30 DBC is independent of SIRT1.
The first 150 amino acids of p30 DBC has been shown to interact with ERalpha through its hormone-binding domain in an estrogen-independent manner. The interaction between p30 DBC and ERalpha could stabilize ERalpha and promote breast cancer cell survival.
In addition to regulating ERalpha activity, p30 DBC could also act as an androgen receptor (AR) coactivator. The ligand binding domain (LBD) of AR interacts with the N-terminus of p30 DBC (residues 1~265) in the presence of AR ligand. This interaction enhances AR-DNA binding and facilitates ARs transcriptional activity. Knocking-down of p30 DBC decreases the induction of AR target genes including prostate specific antigen (PSA) in LNCaP prostate cancer cells.

Homology

Homologs were found in mammals. No p30 DBC homologs was identified in lower organism so far.

Implicated in

Entity name
Breast and prostate carcinomas
Note
p30 DBC was initially identified to be downregulated in some breast and lung cancer specimens. However, in contrast to these findings, several microarray studies showed that p30 DBC mRNA is upregulated in breast cancers. In addition, p30 DBC1 could enhance ERalpha and AR signaling and promotes breast and prostate cancer cell proliferation. Therefore, p30 DBC gene could play a role in tumorigenesis based on in vitro studies, however, its function in cancer etiology remain to be verified in vivo.
Prognosis
High expression of p30 DBC is associated with poor prognosis and metastasis of breast carcinoma.

Bibliography

Pubmed IDLast YearTitleAuthors
184180692008Analysis of DBC1 and its homologs suggests a potential mechanism for regulation of sirtuin domain deacetylases by NAD metabolites.Anantharaman V et al
195091392009Expression of DBC1 and SIRT1 is associated with poor prognosis of gastric carcinoma.Cha EJ et al
210305952010HDAC3 is negatively regulated by the nuclear protein DBC1.Chini CC et al
200717792010Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice.Escande C et al
191265412009Deleted in breast cancer 1, a novel androgen receptor (AR) coactivator that promotes AR DNA-binding activity.Fu J et al
191313382009Identification and characterization of a novel nuclear protein complex involved in nuclear hormone receptor-mediated gene regulation.Garapaty S et al
123704192002DBC2, a candidate for a tumor suppressor gene involved in breast cancer.Hamaguchi M et al
201607192010Identification of DBC1 as a transcriptional repressor for BRCA1.Hiraike H et al
215967822011Reciprocal roles of DBC1 and SIRT1 in regulating estrogen receptor α activity and co-activator synergy.Yu EJ et al
196572302009p30 DBC is a potential regulator of tumorigenesis.Kim JE et al
173145112007Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach.Koch HB et al
210568972011Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma.Lee H et al
192182362009Inhibition of SUV39H1 methyltransferase activity by DBC1.Li Z et al
204791232010MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair.Sharma GG et al
158247302005Caspase-dependent processing activates the proapoptotic activity of deleted in breast cancer-1 during tumor necrosis factor-alpha-mediated death signaling.Sundararajan R et al
174732822007Modulation of estrogen receptor alpha protein level and survival function by DBC-1.Trauernicht AM et al
182355022008Negative regulation of the deacetylase SIRT1 by DBC1.Zhao W et al

Other Information

Locus ID:

NCBI: 57805
MIM: 607359
HGNC: 23360
Ensembl: ENSG00000158941

Variants:

dbSNP: 57805
ClinVar: 57805
TCGA: ENSG00000158941
COSMIC: CCAR2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000158941ENST00000308511Q8N163
ENSG00000158941ENST00000389279Q8N163
ENSG00000158941ENST00000518989H0YC69
ENSG00000158941ENST00000520738H0YB24
ENSG00000158941ENST00000520861G3V119
ENSG00000158941ENST00000521301E5RHH8
ENSG00000158941ENST00000521837E5RGU7
ENSG00000158941ENST00000522599E5RHJ4
ENSG00000158941ENST00000523349E5RFJ3
ENSG00000158941ENST00000523801H0YC58
ENSG00000158941ENST00000613179A0A087X2B6

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to heat stressREACTOMER-HSA-3371556
Regulation of HSF1-mediated heat shock responseREACTOMER-HSA-3371453

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
182355012008DBC1 is a negative regulator of SIRT1.249
182355022008Negative regulation of the deacetylase SIRT1 by DBC1.220
195091392009Expression of DBC1 and SIRT1 is associated with poor prognosis of gastric carcinoma.87
200717792010Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice.87
224466262012DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation.51
225532022012Role of deleted in breast cancer 1 (DBC1) protein in SIRT1 deacetylase activation induced by protein kinase A and AMP-activated protein kinase.48
192182362009Inhibition of SUV39H1 methyltransferase activity by DBC1.45
289734372017Quantitative proteomics reveals that long non-coding RNA MALAT1 interacts with DBC1 to regulate p53 acetylation.44
210305952010HDAC3 is negatively regulated by the nuclear protein DBC1.42
201607192010Identification of DBC1 as a transcriptional repressor for BRCA1.38

Citation

Jian Yuan ; Zhenkun Lou

CCAR2 cell cycle and apoptosis regulator 2

Atlas Genet Cytogenet Oncol Haematol. 2011-07-01

Online version: http://atlasgeneticsoncology.org/gene/46056/ccar2