Download Gene Section KIAA1199 (KIAA1199) Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Short Communication
KIAA1199 (KIAA1199)
Nikki Ann Evensen, Cem Kuscu, Jian Cao
Stony Brook University, Stony Brook, New York, USA (NAE, CK, JC)
Published in Atlas Database: October 2013
Online updated version : http://AtlasGeneticsOncology.org/Genes/KIAA1199ID51053ch15q25.html
DOI: 10.4267/2042/53643
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Other names: CCSP1, TMEM2L
HGNC (Hugo): KIAA1199
Location: 15q25.1
Note
Reported in the Human Unidentified Gene-Encoded
Large Proteins (HUGE) database as KIAA1199.
introns. The transcriptional start site is within the
second exon. There is a canonical TATA-box
present in the KIAA1199 promoter region at -31 to
-27 base pairs, as well as a GC-box at -248 to -243
base pairs. However, this GC-box was not found to
be required for transcriptional activation of
KIAA1199, nor was there any methylation of the
cytosines found within this region, which is often
an important feature of GC-boxes. KIAA1199 also
contains a CpG island within the first intron (+525
50 +1025). The methylation status of this CpG
island was found to effect the expression level of
KIAA1199, with high levels of DNA methylation
found in non-aggressive, low expressing, cancer
cell lines (Kuscu et al., 2012).
DNA/RNA
Transcription
Abstract
Review on KIAA1199, with data on DNA/RNA, on
the protein encoded and where the gene is
implicated.
Identity
An AP-1 binding site, located between -48 and -45
within the KIAA1199 promoter, was found to be
important for KIAA1199 promoter activity. AP-1
was found to directly bind to this region in order to
activate transcription of KIAA1199.
Description
The human KIAA1199 transcript spans 7080 base
pairs on chromosome 15 in the region 15q25.1. It
contains 29 exons, 28 of which are coding, and 28
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
324
KIAA1199 (KIAA1199)
Evensen NA, et al.
AP-1 transcription factors have been associated
with increased promoter activity of genes
associated with cancer. Additionally, among four
potential NF-κB binding sites, the site furthest from
the transcriptional start site (-1345 to -1333) was
found to play a role in KIAA1199 promoter
activation. NF-κB was found to directly bind to this
site to increase transcription of KIAA1199 (Kuscu
et al., 2012).
(BiP)/glucose-regulated protein (GRP-78), which
further supports the ER localization of KIAA1199
(Evensen et al., 2013). Secretion of KIAA1199 has
also been demonstrated for certain cell types
(Tiwari et al., 2013).
Function
KIAA1199 plays a key role in cancer progression
via increasing cancer cell migration and invasion,
which are necessary steps for cancer metastasis.
Expression of KIAA1199 in non-aggressive cancer
cell lines leads to an epithelial-to-mesenchymal
transition along with increased migratory
capabilites. Furthermore, knockdown of KIAA1199
leads to a loss of mesenchymal characteristics with
decreased invasive and migratory abilities, as well
as reduced metastastic potential (Evensen et al.,
2013).
A role for KIAA1199 in maintaining ion
homeostasis, and more specifically calcium
signaling, has also been suggested (Abe et al.,
2003; Tiwari et al., 2013). KIAA1199-mediated
migration was found to involve elevated cytosolic
calcium levels followed by protein kinase C alpha
(PKCα) translocation/activation. This change in
cytosolic calcium is due to increased release of
calcium from the ER via an unknown mechanism
induced by KIAA1199 (Evensen et al., 2013).
Additional studies revealed an interaction with
KIAA1199 and inositol 1,4,5-triphosphate receptor
3 (ITPR3) which is a ligand-gated ion channel
located on the ER membrane that is known to
mediate the release of calcium from the ER (Tiwari
et al., 2013).
KIAA1199 is thought to be a target of the Wnt
signaling pathway and a potential player in the
progression of colorectal adenomatous (SabatesBellver et al., 2007; Tiwari et al., 2013).
Additionally, silencing of KIAA1199 was shown to
alter the expression of genes known to be involved
in the Wnt/β-catenin pathway and decrease cell
proliferation (Birkenkamp-Demtroder et al., 2011).
In human skin fibroblasts, KIAA1199 expression
was found to cause increased degradation of
hyaluronan (HA), which is a glycosaminoglycan
found in the extracellular matrix surrounding
tissues. It acts as a structural component and can
affect cell signaling and cellular behavior, including
angiogenesis and cell migration (Yoshida et al.,
2013).
Protein
Description
The KIAA1199 open reading frame consists of
4083 base pairs, which encodes a protein 1361
amino acids in length. It has a predicted molecular
weight of approximately 163 kDa. The KIAA1199
protein has a G8 domain between a.a. 44-166,
which is a novel domain that contains eight
conserved glycines and consists of five β-strand
pairs (He et al., 2006). Several disease related
proteins contain this domain, including polyductin
protein (PKHD1) and transmembrane protein 2
(TMEM2), although the exact function of the G8
motif remains unclear (He et al., 2006). A GG
domain, characterized by seven β-strands and two
α-helices, can also be found within the KIAA1199
protein (Guo et al., 2006). This novel domain also
has no known function. KIAA1199 is also predicted
to have a cleavable signal peptide at its NH2terminus (Sabates-Bellver et al., 2007). KIAA1199
has been demonstrated to be N-linked glycosylated
(Tiwari et al., 2013).
Expression
Northern blot analysis of normal human tissues
revealed expression of KIAA1199 mRNA in
various tissues, with the highest levels found in the
brain, placenta, lung, and testis (Michishita et al.,
2006). KIAA1199 is also expressed in various cell
types found in the inner ear (Abe et al., 2003;
Usami et al., 2008), and in dermal fibroblasts of the
skin (Yoshida et al., 2013). Increased levels of
KIAA1199 have also been demonstrated in
numerous cancer tissues compared to normal
tissues, including colorectal adenomas (SabatesBellver et al., 2007).
Localisation
Cytoplasmic and nuclear staining for KIAA1199
has been observed in gastric and colon cancer tissue
samples (Sabates-Bellver et al., 2007; Matsuzaki et
al., 2009; Birkenkamp-Demtroder et al., 2011).
More detailed subcellular localization revealed
expression of exogenous and endogenous
KIAA1199 within the endoplasmic reticulum (ER)
of various cell types (Evensen et al., 2013; Tiwari
et al., 2013). KIAA1199 was found to interact with
the ER chaperone binding immunoglobulin protein
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
Homology
The KIAA1199 gene product shares 38% identity
(63% similarity) with transmembrane protein 2
(TMEM2). A small region within the KIAA1199
gene product (aa 55-155) also shares 38% identity
(57% similarity) with polyductin protein (PKHD1)
(Abe et al., 2003). However, none of these
homologies revealed any functional information.
325
KIAA1199 (KIAA1199)
Evensen NA, et al.
Mutations
non-syndromic hearing loss diseases. FEBS Lett. 2006
Jan 23;580(2):581-4
Somatic
He QY, Liu XH, Li Q, Studholme DJ, Li XW, Liang SP. G8:
a novel domain associated with polycystic kidney disease
and non-syndromic hearing loss. Bioinformatics. 2006 Sep
15;22(18):2189-91
Nine DNA variants of the KIAA1199 gene were
identified, six of which were missense (R187C,
R187H, H783R, H783Y, V1109I, and P1169A) and
three of which were synonymous substitutions
(L532L, P619P, D800D). R187C, R187H, H783Y,
and V1109I were found only in families with
nonsyndromic hearing loss, suggesting a potential
role for these specific mutations in this disease state
(Abe et al., 2003).
Michishita E, Garcés G, Barrett JC, Horikawa I.
Upregulation of the KIAA1199 gene is associated with
cellular mortality. Cancer Lett. 2006 Jul 28;239(1):71-7
Sabates-Bellver J, Van der Flier LG, de Palo M, Cattaneo
E, Maake C, Rehrauer H, Laczko E, Kurowski MA, Bujnicki
JM, Menigatti M, Luz J, Ranalli TV, Gomes V, Pastorelli A,
Faggiani R, Anti M, Jiricny J, Clevers H, Marra G.
Transcriptome profile of human colorectal adenomas. Mol
Cancer Res. 2007 Dec;5(12):1263-75
Implicated in
Usami S, Takumi Y, Suzuki N, Oguchi T, Oshima A,
Suzuki H, Kitoh R, Abe S, Sasaki A, Matsubara A. The
localization of proteins encoded by CRYM, KIAA1199,
UBA52, COL9A3, and COL9A1, genes highly expressed in
the cochlea. Neuroscience. 2008 Jun 12;154(1):22-8
Gastric and colorectal cancers
Prognosis
Numerous studies have implicated KIAA1199
expression with cancer progression. Gastric cancer
patients with low expression of KIAA1199 were
found to have significantly better overall 5-year
survival rates as compared to those expressing
higher levels. Furthermore, lymph node metastasis,
distant metastasis, and peritoneal dissemination
were more often observed in the patients with
higher levels of KIAA1199 (Matsuzaki et al.,
2009).
Additionally, there is evidence to suggest that
KIAA1199 could potentially be used as a
biomarker for cancer. Higher levels of KIAA1199
transcripts were found in the serum of patients with
adenoma and colorectal cancer as compared to
neoplasia free controls (LaPointe et al., 2012).
KIAA1199 was also found to be upregulated in
cancerous tissues from gastric adenocarcinoma
patients, further supporting the idea of using
KIAA1199 for diagnostics, early detection, or as a
predictor of cancer progression (Chivu Economescu
et al., 2010).
Matsuzaki S, Tanaka F, Mimori K, Tahara K, Inoue H, Mori
M.
Clinicopathologic
significance
of
KIAA1199
overexpression in human gastric cancer. Ann Surg Oncol.
2009 Jul;16(7):2042-51
Chivu Economescu M, Necula LG, Dragu D, Badea L,
Dima SO, Tudor S, Nastase A, Popescu I, Diaconu CC.
Identification of potential biomarkers for early and
advanced
gastric
adenocarcinoma
detection.
Hepatogastroenterology. 2010 Nov-Dec;57(104):1453-64
Birkenkamp-Demtroder K, Maghnouj A, Mansilla F,
Thorsen K, Andersen CL, Øster B, Hahn S, Ørntoft TF.
Repression of KIAA1199 attenuates Wnt-signalling and
decreases the proliferation of colon cancer cells. Br J
Cancer. 2011 Aug 9;105(4):552-61
Kuscu C, Evensen N, Kim D, Hu YJ, Zucker S, Cao J.
Transcriptional and epigenetic regulation of KIAA1199
gene expression in human breast cancer. PLoS One.
2012;7(9):e44661
LaPointe LC, Pedersen SK, Dunne R, Brown GS, Pimlott
L, Gaur S, McEvoy A, Thomas M, Wattchow D, Molloy PL,
Young GP. Discovery and validation of molecular
biomarkers for colorectal adenomas and cancer with
application to blood testing. PLoS One. 2012;7(1):e29059
Evensen NA, Kuscu C, Nguyen HL, Zarrabi K, Dufour A,
Kadam P, Hu YJ, Pulkoski-Gross A, Bahou WF, Zucker S,
Cao J. Unraveling the role of KIAA1199, a novel
endoplasmic reticulum protein, in cancer cell migration. J
Natl Cancer Inst. 2013 Sep 18;105(18):1402-16
Nonsyndromic hearing loss
Prognosis
Several mutations within KIAA1199 were found in
patients with nonsyndromic hearing loss but not in
control subjects. Based on the expression pattern of
KIAA1199 in the cells of the inner ear, it is thought
that it could play a role in normal auditory
development with these particular mutations having
a negative impact (Abe et al., 2003).
Tiwari A, Schneider M, Fiorino A, Haider R, Okoniewski
MJ, Roschitzki B, Uzozie A, Menigatti M, Jiricny J, Marra
G. Early insights into the function of KIAA1199, a markedly
overexpressed protein in human colorectal tumors. PLoS
One. 2013;8(7):e69473
Yoshida H, Nagaoka A, Kusaka-Kikushima A, Tobiishi M,
Kawabata K, Sayo T, Sakai S, Sugiyama Y, Enomoto H,
Okada Y, Inoue S. KIAA1199, a deafness gene of
unknown function, is a new hyaluronan binding protein
involved in hyaluronan depolymerization. Proc Natl Acad
Sci U S A. 2013 Apr 2;110(14):5612-7
References
Abe S, Usami S, Nakamura Y. Mutations in the gene
encoding KIAA1199 protein, an inner-ear protein
expressed in Deiters' cells and the fibrocytes, as the cause
of nonsyndromic hearing loss. J Hum Genet.
2003;48(11):564-70
This article should be referenced as such:
Evensen NA, Kuscu C, Cao J. KIAA1199 (KIAA1199).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):324326.
Guo J, Cheng H, Zhao S, Yu L. GG: a domain involved in
phage LTF apparatus and implicated in human MEB and
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
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