Download Gene Section KIAA1967 (KIAA1967) Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
KIAA1967 (KIAA1967)
Jian Yuan, Zhenkun Lou
Division of Oncology Research, Mayo Clinic, Rochester, MN 55902, USA (JY, ZL)
Published in Atlas Database: July 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/KIAA1967ID46056ch8p21.html
DOI: 10.4267/2042/46086
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
DNA/RNA
Other names: DBC-1; DBC1; NET35; p30DBC
HGNC (Hugo): KIAA1967
Location: 8p21.3
Description
This gene can be found on chromosome 8 at location
22462539-22477984.
Adapted from http://genome.ucsc.edu.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
1038
KIAA1967 (KIAA1967)
Yuan J, Lou Z
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 AR's
transcriptional activity. Knocking-down of p30 DBC
decreases the induction of AR target genes including
prostate specific antigen (PSA) in LNCaP prostate
cancer cells.
Transcription
The DNA sequence contains 21 exons and the
transcript length is 4012 bps translated to a 923
residues protein.
Protein
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 Cterminal 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).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
Homology
Homologs were found in mammals. No p30 DBC
homologs was identified in lower organism so far.
Implicated in
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.
References
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Yuan J, Lou Z
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This article should be referenced as such:
Yuan J, Lou Z. KIAA1967 (KIAA1967). Atlas Genet Cytogenet
Oncol Haematol. 2011; 15(12):1038-1040.
Kim JE, Chen J, Lou Z. p30 DBC is a potential regulator of
tumorigenesis. Cell Cycle. 2009 Sep 15;8(18):2932-5
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
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