Download Gene Section UBD (ubiquitin D) Atlas of Genetics and Cytogenetics

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Gene Section
Review
UBD (ubiquitin D)
Joan Oliva, Samuel W French
Department of Hematology, LA Biomed, Torrance, CA 90502, USA (JO), Department of Pathology, LA
BioMed, Torrance, CA 90502, USA (SWF)
Published in Atlas Database: November 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/UBDID43742ch6p22.html
DOI: 10.4267/2042/47304
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Transcription
Other names: FAT10, GABBR1, UBD-3
HGNC (Hugo): UBD
Location: 6p22.1
In a centromeric to telomeric orientation; transcription
is cell-cycle regulated, with down regulation during the
G1 and G2/M phase and it is regulated by
inflammatory cytokines (e.g. TNFa and IFNg).
Pseudogene
DNA/RNA
UBDP1 ubiquitin D pseudogene 1, Locus ID 387062,
Location 6p22.1.
LOC100286971 ubiquitin D pseudogene, Locus ID
100286971, Location 6p22.1.
Description
2 exons on 4,3 kb.
The upper part of the diagram shows the loci of UbD, present in the MHCI locus of chromosome 6. The lower part of the diagram shows
the mRNA of UBD.
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UBD (ubiquitin D)
Oliva J, French SW
hydrophobic to small and polar. No report showed a
link between this polymorphism and a disease.
A missense mutation was observed in the position 95 of
the protein S95P. Due to this mutation the protein goes
from small size and polar to medium size and
hydrophobic. No report showed a link between this
polymorphism and a disease.
A missense mutation was observed in the position 99 of
the protein A99G. Due to this mutation the protein goes
from small size and hydrophobic to glycine. No report
showed a link between this polymorphism and a
disease.
A missense mutation was observed in the position 120
of the protein E120K. Due to this mutation the protein
goes from medium size and acidic to large size and
basic. No report showed a link between this
polymorphism and a disease.
A missense mutation was observed in the position 160
of the protein C160S. Due to this mutation the protein
goes from medium size and polar to small size and
polar. No report showed a link between this
polymorphism and a disease.
A mutation in UBD I68T was significantly associated
with advanced stages of colorectal cancer and with
colorectal below 65 years of age.
Protein
Description
165 amino acids; 18 kDa protein; different post
translational
modifications:
Acetylation,
phosphorylation, ubiquitination. UBD contains 2
ubiquitin domains, with 2 potential K involved in its
ubiquitination but not in its degradation. UBD contains
from N-Term to C-Term, an Ubiquitin like domain (2176) containing K55 equivalent of the K48 of ubiquitin,
an ubiquitin like domain (104-165) containing K137
equivalent of the K48 of ubiquitin. In C-terminal, UBD
contains a GG motif, equivalent to Ubiquitin GG motif,
important for conjugating proteins: TP53, USE.
Expression
Lung, brain, kidney, liver, spleen, thymus, gut, testis,
lymph nodes, uterus and ovaries.
Localisation
Nuclear and cytoplasmic.
Function
UBD is involved in the immune response (expressed in
spleen, thymus, and lymph nodes, involved in
immunoproteasome formation and in antigen
presentation). UBD is degradated by the proteasome,
independently of ubiquitin pathway, but it targets also
proteins to the proteasome for degradation. UBD plays
a critical role in the cell cycle pro-apoptotic (by over
expression, by interacting with HIV VpR), antiapoptotic (spleens, thymuses and bone marrow), antiproliferative (when induced by retinoids acid), proproliferative (in colon and liver cancer, maybe by
interacting with MAD2 and p53, cancers in liver and
colon).
Implicated in
Colon cancer
Disease
Colorectal carcinoma (CRE) is one of the most
common cancers encountered in the western world and
increasingly in the developing world as well. Colorectal
carcinoma has a high morbidity and mortality rate.
Colorectal cancer is mainly associated with the
mutation of adenomatous polyposis coli (APC).
Patients with ulcerative colitis and Crohn's disease are
at increased risk for developing colorectal cancer
(CRC). Chronic inflammation is believed to promote
carcinogenesis, and per consequence the increases of
UBD expression. UBD could be used as a new
prognostic marker for the recurrence of stage II and III
of colon cancer.
Prognosis
The prognosis is highly dependent on the stage of the
colorectal cancer (from over 90% of survival after 5
years for Stage I to less than 5% of survival, after 5
years, for Stage IV).
Homology
With Ubiquitin.
Mutations
Germinal
N/A
Somatic
A missense mutation was observed in the position 376
of the mRNA changing TTG in TCG (L51S). Due to
this mutation the protein goes from medium size and
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UBD (ubiquitin D)
Oliva J, French SW
The mutations in yellow are the missense mutation. The mutation in red is the I68T, associated with advanced stages of colorectal
cancer.
50% to 80%, after 5 years.
Hybrid/Mutated gene
N/A
Abnormal protein
N/A
Oncogenesis
The real mechanism associating UBD expression and
liver cancer is not well defined. However, an
inflammatory reaction induces the up regulation of the
expression of UBD. UBD amplifies the inflammatory
reaction by mediating NF-Kb activation, amplifiying
the inflammatory response that is known to be a cause
of the cancer.
Cytogenetics
Microsatellite Instability (15-20% of the sporadic
colorectal cancers), Chromosomal instability (in 8085% of the colorectal cancers), CpG island methylator
phenotype.
Loss of chromosome: 1p, 1p3, 1q22, 4, 4q26, 5, 5q, 8p,
10, 14, 15, 15q11-q21, 17, 17p, 17p12-13, 17q10, 18,
18p, 18p21-pter, 18q, 18q10, 18q21, 18q12-21, 21, 22,
Y.
Gain of chromosome: 1q11, 3, 3q, 5, 5p, 5q, 6, 7, 8, 8q,
8q28, 8q23-ter, 12, 12p, 13, 13p14-31, 13q, 16q24.3,
17p, 17q, 19, 20, 20q, 20q13, X.
Hybrid/Mutated gene
PMS2CL
Oncogenesis
An inflammatory reaction induces the up regulation of
the expression of UBD. UBD amplified the
inflammatory reaction by mediating NF-Kb activation.
Carriage of the minor allele of UBD I68T was
significantly associated with advanced stages of CRC
and with CRC below 65 years of age.
Celiac disease (6p21.3)
Disease
Celiac disease (CD) is a disorder of the small intestine,
resulting from the intolerance of different food:
prolamins, wheat, barley, rye, gluten sensitive
enteropathy. The presence of specific HLA-DQ alleles,
on chromosome 6p21.3, increases the susceptibility to
celiac disease. This region has been designated
CELIAC1. The original pathogenic mechanism of the
CD is still unknown. However, it is clear that the
immune system is involved. CD is associated with the
presence of one copy of the HLA-DQ2 heterodimer and
less frequently in 6% of the patients with the HLADQ8 molecule. The up regulation of UBD is associated
with intestinal mucosa of active CD.
Prognosis
Very poor (response to removing glutens from the
diet).
Cytogenetics
1p36, 4p15, 5q31, 6p21.3, 7q21, 9p21-23 and 16q12
chromosomal regions are involved in Celiac disease.
Hybrid/Mutated gene
N/A
Abnormal protein
N/A
Oncogenesis
N/A
Gastric cancer
Disease
Gastric cancer is one of the most common malignant
tumors in the world. The mortality of the gastric cancer
is very high (especially in East Asia). The expression of
UBD is upregulated in the gastric tumors and
associated with a low survival rate, after the surgery.
The upregulation of UBD is associated with a nonactive mutant of p53, leading to the formation of the
gastric cancer.
Prognosis
Poor.
Cytogenetics
Gains of 3q, 7p, 7q, 8q, 13q, 17q, 20p. Losses of 4q,
9p, 17p and 18q.
Liver cancer
Disease
Human hepatocellular carcinoma (HCC) is the 5th most
common cancer in the world and the 3rd cause of
cancer mortality (high incidence in South East Asia and
central Africa). The causes of HCC are due to genetic
mutations, HBV or HCV infection, alcohol, toxin
exposures (e.g. aflotoxins), obesity, diabetes,
hemochromatosis. UBD is over expressed in more than
60% of HCC. UBD is also overexpressed in more than
75% of liver cancer stem cells.
Prognosis
With a liver transplant, the survival rates varies from
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(4)
HIV associated nephropathy
Disease
HIV-associated nephropathy (HIVAN) is a kidney
disease in patients with human immunodeficiency virus
(HIV) disease. HIVAN is characterized by a nephrotic
range proteinuria (associated with UBD over
expression), azotemia, normal to large kidneys, focal
segmental glomerulosclerosis. UBD is overexpressed in
291
UBD (ubiquitin D)
Oliva J, French SW
Ji F, Jin X, Jiao CH, Xu QW, Wang ZW, Chen YL. FAT10 level
in human gastric cancer and its relation with mutant p53 level,
lymph node metastasis and TNM staging. World J
Gastroenterol. 2009 May 14;15(18):2228-33
HIVAN and induces apoptosis by its interaction with
HIV protein Vpr.
Prognosis
Very poor prognosis without HIV treatment. Good
prognosis with HIV treatment.
Gong P, Canaan A, Wang B, Leventhal J, Snyder A, Nair V,
Cohen CD, Kretzler M, D'Agati V, Weissman S, Ross MJ. The
ubiquitin-like protein FAT10 mediates NF-kappaB activation. J
Am Soc Nephrol. 2010 Feb;21(2):316-26
Graft versus host reaction
Prognosis
The survival average is from 15 to 50% at 5 years. The
over expression of UBD is observed during graft versus
host disease. UBD could be involved or serve as a
molecular marker for graft versus host disease and graft
versus host reaction.
Yagil Y, Hessner M, Schulz H, Gosele C, Lebedev L, Barkalifa
R, Sapojnikov M, Hubner N, Yagil C. Geno-transcriptomic
dissection of proteinuria in the uninephrectomized rat uncovers
a molecular complexity with sexual dimorphism. Physiol
Genomics. 2010 Nov 29;42A(4):301-16
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Atlas Genet Cytogenet Oncol Haematol. 2012; 16(4)
This article should be referenced as such:
Oliva J, French SW. UBD (ubiquitin D). Atlas Genet Cytogenet
Oncol Haematol. 2012; 16(4):289-292.
292