Download Gene Section MUC16 (mucin 16, cell surface associated) in Oncology and Haematology

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in Oncology and Haematology
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MUC16 (mucin 16, cell surface associated)
Shantibhusan Senapati, Moorthy P Ponnusamy, Ajay P Singh, Maneesh Jain, Surinder K Batra
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870
Nebraska Medical Center, Durham Research center 7005, Omaha, NE 68198-5870, USA
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/MUC16ID41455ch19q13.html
DOI: 10.4267/2042/38525
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
approximatively 179 kb of genomic DNA.
Identity
Transcription
Hugo: MUC16
Other names: CA125; FLJ14303; Mucin-16
Location: 19p13.2
Note: MUC16 belongs to the subgroup of the
membrane-anchored mucin. It is a type-1 glycopotein
with heavy O- and N-type glycosylation.
As per the present available information, there is a
discrepancy regarding the total number of exons
present in MUC16 genomic DNA. This discrepancy is
due to the absence/presence of some of the genomic
sequences (particularly for the repeat regions) in the
available genomic databases. The terminal nine exons
on both 5' and 3' ends code for the amino- and carboxyterminal domains of MUC16, respectively. At the same
time, it has been proposed that five consecutive exons
code for a single repeat unit (SRU) of the central
tandem repeat domain.
DNA/RNA
Description
In the genome, MUC16 is localized in 19p13.2
chromosome and is coded by sequences present within
Shows the genomic organization of MUC16 gene.
Protein
Shows the structural organization of CA125/MUC16 protein.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
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MUC16 (mucin 16, cell surface associated)
Senapati S, et al.
Description
Function
MUC16 protein harbors a central tandem repeat region,
N-terminal domain and carboxy terminal domain. The
N-terminal domain has 12070 numbers of amino acids
rich in serine/threonine residues and accounts for the
major O-glycosylation known to be present in CA125.
The MUC16 protein back bone is dominated by tandem
repeat region, which has more than 60 repeat domains,
each composed of 156 amino acids. Though all the
individual repeat units are not similar, most of them
occur more than once in the sequence.
The repeat units are rich in serine, threonine and
proline residues, which are typical for any mucins.
Each repeat unit has some homology to the SEA (Seaurchin sperm protein, Enterokinase and Agrin) module,
whose exact biological function is not known.
The epitopes for known anti-CA125 antibodies (OC125
and M11) are thought to be present on a small cysteine
ring region present in the tandem-repeat region of
MUC16.
The carboxy-terminal domain has 284 aminoacids and
can be divided into three different regions: extra
cellular, transmembrane and cytoplasmic tail. The
extracellular part of the carboxy-terminal domain has
many N-glycosylation sites and some O-glycosyaltion
sites. Several in silico analyses suggest a putative
cleavage site in the extracellular part of carboxyterminal domain. The MUC16 cytoplasmic tail is 31
amino acids long and has many possible
phosphorylation sites.
The phosphorylation of CA125 in WISH cells has been
reported
by
labeling
with
32PO43and
immunoprecipitaion analysis but the exact site of
phosphorylation is yet to be mapped. Interestingly,
CA125 contains a putative tyrosine phosphorylation
site (RRKKEGY), which was first recognized in Src
family protein. This sequence is conserved in the
translated mouse EST (AK003577) that has homology
with CA125/MUC16 at the C-terminal end. Recently, it
has been shown that MUC16 cytoplasmic tail, which
contains a polybasic aminoacid sequence, interacts with
cytoskeleton through ERM (ezrin/radixin/moesin)
actin-binding proteins.
MUC16 provides a disadhesive protective barrier to the
ocular epithelial surface. Overexpression of
CA125/MUC16 in ovarian cancer indicates its possible
role in cancer pathogenesis. Studies have shown that
CA125/MUC16 binds to mesothelin and galectin-1,
which are overexpressed in ovarian cancer. It has also
been shown that mesothelin-MUC16 interaction has
significance in adhesion of ovarian cancer cells to
mesothelial cells present on the inner wall of the
peritoneum and on the surface of other abdominal
organs. This cell to cell adhesion may help in ovarian
cancer metastasis. It has been proposed that galectin-1
bound to MUC16 may cause apoptosis of T cells, and
thus help in the suppression of the host immunity.
Homology
Similar to mucin 16 of Pan troglodytes, Canis lupus
familiaris, Mus musculus, Rattus norvegicus and Gallus
gallus.
Implicated in
Ovarian cancer
Disease
Epithelial ovarian cancer is the most lethal
gynaecologic malignancy in the United States and other
parts of the world. In the United States, ovarian cancer
accounts for approximately 22,000 new cases and
16,000 deaths occurring every year. The epithelial
ovarian carcinomas represent approximately 90% of all
types of ovarian malignant neoplasms. Due to lack of
specific signs and symptoms of this disease, coupled
with lack of reliable screening strategies most patients
are diagnosed in the advanced stage of the disease,
resulting in low overall cure rates. Ovarian cancer
patients are generally treated with surgical resection
and subsequent platinum-based chemotherapy.
Although, many patients initially respond well to
chemotherapy, long term survival remains poor due to
eventual tumor recurrence and emergence of drugresistant disease. Overall, the five year survival rate is
45%.
Prognosis
Since the last 20 years, CA125/MUC16 has been used
as a well-established marker for diagnosis of ovarian
cancer. It is mostly overexpressed in serous type of
ovarian cancers and less likely to be expressed in
mucinous tumors. More than 80% of ovarian cancer
patients have elevated CA125 level during their
treatment period. It has been shown that the disease
progression is associated with an increase in serum
CA125 level, while a decline in serum CA125 level is
associated with response to therapy. In another finding,
Expression
The expression of MUC16 has been reported in human
epithelia of conjunctiva, cornea, middle ear and trachea
under normal physiological conditions. MUC16 is also
expressed in ovarian carcinoma.
Localisation
It is a type I membrane-bound protein and due to
cleavage gets secreted into the extracellular space. On
the ocular surface, MUC16 is expressed on the tips of
the microplicae of the ocular surface.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
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MUC16 (mucin 16, cell surface associated)
Senapati S, et al.
it has been shown that the trend of serum CA125 level
during the first three courses of chemotherapy is a
strong forecaster of re-examination findings in patients
with ovarian carcinoma at the end of treatment.
Interestingly, it has been shown that a normal CA125
level by the end of second or third chemotherapy is
strongly linked to the survival of patients in stage 3 or
stage 4 conditions. Also, variations in the CA125 value
even within the normal range carry useful information
regarding prediction of time to treatment failure.
Additionally, in patients in stage 1 cancers it has been
suggested that CA125 elevations are not related to the
tumor mass volume. Recently, the potential of
CA125/MUC16 as a therapeutic target has been
harnessed by using an armed human antibody (3A5)
against MUC16 protein.
Oncogenesis
There is no experimental evidence in the scientific
literature for a role of MUC16 in oncogenesis.
However, MUC16 possesses many structural
similarities with other membrane bound mucins, like
MUC1 and MUC4, which are already shown to be
functionally
involved
in
different
cancers.
Transmembrane mucins are hypothesized to serve as
sensors of the external environment and can transduce
signals via the post-translational modifications of their
cytoplasmic tail. Phosphorylation of MUC16 protein
has already been reported. Though the exact interacting
partner and the site of phosphorylation are unknown,
the presence of potential phosphorylation sites in
MUC16 cytoplasmic tail indicates the possible role of
MUC16 in downstream signal transduction. Further, it
has been shown that MUC16 interacts with galectin-1
and mesothelin and these interactions may have a role
in cancer progression.
O'Brien TJ, Beard JB, Underwood LJ, Shigemasa K. The CA
125 gene: a newly discovered extension of the glycosylated Nterminal domain doubles the size of this extracellular
superstructure. Tumour Biol 2002;23(3):154-169.
References
Davies JR, Kirkham S, Svitacheva N, Thornton DJ, Carlstedt I.
MUC16 is produced in tracheal surface epithelium and
submucosal glands and is present in secretions from normal
human airway and cultured bronchial epithelial cells. Int J
Biochem Cell Biol 2007;39(10):1943-1954.
Yin BW, Dnistrian A, Lloyd KO. Ovarian cancer antigen CA125
is encoded by the MUC16 mucin gene. Int J Cancer
2002;98(5):737-740.
Seelenmeyer C, Wegehingel S, Lechner J, Nickel W. The
cancer antigen CA125 represents a novel counter receptor for
galectin-1. J Cell Sci 2003;116(Pt 7):1305-1318.
Maeda T, Inoue M, Koshiba S, Yabuki T, Aoki M, Nunokawa E,
Seki E, Matsuda T, Motoda Y, Kobayashi A, Hiroyasu F,
Shirouzu M, Terada T, Hayami N, Ishizuka Y, Shinya N,
Tatsuguchi A, Yoshida M, Hirota H, Matsuo Y, Tani K,
Arakawa T, Carninci P, Kawai J, Hayashizaki Y, Kigawa T,
Yokoyama S. Solution structure of the SEA domain from the
murine homologue of ovarian cancer antigen CA125 (MUC16).
J Biol Chem 2004;279(13):13174-13182.
Chauhan SC, Singh AP, Ruiz F, Johansson SL, Jain M, Smith
LM, Moniaux N, Batra SK. Aberrant expression of MUC4 in
ovarian carcinoma: diagnostic significance alone and in
combination with MUC1 and MUC16 (CA125). Mod Pathol
2006;19(10):1386-1394.
Duraisamy S, Ramasamy S, Kharbanda S, Kufe D. Distinct
evolution of the human carcinoma-associated transmembrane
mucins, MUC1, MUC4 AND MUC16. Gene 2006;373:28-34.
Gubbels JA, Belisle J, Onda M, Rancourt C, Migneault M, Ho
M, Bera TK, Connor J, Sathyanarayana BK, Lee B, Pastan I,
Patankar MS. Mesothelin-MUC16 binding is a high affinity, Nglycan dependent interaction that facilitates peritoneal
metastasis of ovarian tumors. Mol Cancer 2006;5(1):50.
Blalock TD, Spurr-Michaud SJ, Tisdale AS, Heimer SR,
Gilmore MS, Ramesh V, Gipson IK. Functions of MUC16 in
Corneal Epithelial Cells. Invest Ophthalmol Vis Sci
2007;48(10):4509-4518.
Chen Y, Clark S, Wong T, Chen Y, Chen Y, Dennis MS, Luis
E, Zhong F, Bheddah S, Koeppen H, Gogineni A, Ross S,
Polakis P, Mallet W. Armed antibodies targeting the mucin
repeats of the ovarian cancer antigen, MUC16, are highly
efficacious in animal tumor models. Cancer Res
2007;67(10):4924-4932.
Erratum
in
Cancer
Res
2007;67(12):5998.
O'Brien TJ, Beard JB, Underwood LJ, Dennis RA, Santin AD,
York L. The CA 125 gene: an extracellular superstructure
dominated by repeat sequences. Tumour Biol 2001;22(6):348366.
This article should be referenced as such:
Yin BW, Lloyd KO. Molecular cloning of the CA125 ovarian
cancer antigen: identification as a new mucin, MUC16. J Biol
Chem 2001;276(29):27371-27375.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Senapati S, Ponnusamy MP, Singh AP, Jain M, Batra SK.
MUC16 (mucin 16, cell surface associated). Atlas Genet
Cytogenet Oncol Haematol.2008;12(3):223-225.
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