UBD (ubiquitin D)

2011-11-01   Joan Oliva , Samuel W French 

Department of Hematology, LA Biomed, Torrance, CA 90502, USA (JA); Department of Pathology, LA BioMed, Torrance, CA 90502, USA (SWF)

Identity

HGNC
LOCATION
6p22.1
IMAGE
Atlas Image
LEGEND
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.
LOCUSID
ALIAS
FAT10,GABBR1,UBD-3
FUSION GENES

DNA/RNA

Description

2 exons on 4,3 kb.

Transcription

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

UBDP1 ubiquitin D pseudogene 1, Locus ID 387062, Location 6p22.1.
LOC100286971 ubiquitin D pseudogene, Locus ID 100286971, Location 6p22.1.

Proteins

Atlas Image

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 (21-76) 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), anti-apoptotic (spleens, thymuses and bone marrow), anti-proliferative (when induced by retinoids acid), pro-proliferative (in colon and liver cancer, maybe by interacting with MAD2 and p53, cancers in liver and colon).

Homology

With Ubiquitin.

Mutations

Atlas Image
The mutations in yellow are the missense mutation. The mutation in red is the I68T, associated with advanced stages of colorectal cancer.

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 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.

Implicated in

Entity name
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 Crohns 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).
Cytogenetics
Microsatellite Instability (15-20% of the sporadic colorectal cancers), Chromosomal instability (in 80-85% 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 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.
Entity name
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 non-active 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.
Entity name
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 50% to 80%, after 5 years.
Hybrid gene
N/A
Fusion 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.
Entity name
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 HLA-DQ8 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 gene
N/A
Fusion protein
N/A
Oncogenesis
N/A
Entity name
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 HIVAN and induces apoptosis by its interaction with HIV protein Vpr.
Prognosis
Very poor prognosis without HIV treatment. Good prognosis with HIV treatment.
Entity name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
214825012011Long-term results of liver transplantation.Åberg F et al
109360682000Genetics of hepatocellular carcinoma.Buendia MA et al
175702262007Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.El-Serag HB et al
199597142010The ubiquitin-like protein FAT10 mediates NF-kappaB activation.Gong P et al
194375622009FAT10 level in human gastric cancer and its relation with mutant p53 level, lymph node metastasis and TNM staging.Ji F et al
213963472011FAT10 modifies p53 and upregulates its transcriptional activity.Li T et al
117151132002Genomewide linkage analysis of celiac disease in Finnish families.Liu J et al
102002591999A MHC-encoded ubiquitin-like protein (FAT10) binds noncovalently to the spindle assembly checkpoint protein MAD2.Liu YC et al
214907052011Genetics, cytogenetics, and epigenetics of colorectal cancer.Migliore L et al
213050402011Expression profiling of major histocompatibility and natural killer complex genes reveals candidates for controlling risk of graft versus host disease.Novota P et al
182804692008Fat10 is an epigenetic marker for liver preneoplasia in a drug-primed mouse model of tumorigenesis.Oliva J et al
214114692011Surgical treatment for hepatocellular carcinoma.Takayama T et al
208768442010Geno-transcriptomic dissection of proteinuria in the uninephrectomized rat uncovers a molecular complexity with sexual dimorphism.Yagil Y et al

Other Information

Locus ID:

NCBI: 10537
MIM: 606050
HGNC: 18795
Ensembl: ENSG00000213886

Variants:

dbSNP: 10537
ClinVar: 10537
TCGA: ENSG00000213886
COSMIC: UBD

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000213886ENST00000377050O15205
ENSG00000213886ENST00000377050A0A1U9X8S6

Expression (GTEx)

0
1
2
3
4
5
6
7
8

References

Pubmed IDYearTitleCitations
193038522009Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation.280
191855242009Structural basis for recognition of diubiquitins by NEMO.105
178896732007E1-L2 activates both ubiquitin and FAT10.62
127306732003Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers.55
158314552005FAT10, a ubiquitin-independent signal for proteasomal degradation.55
185744672008Proinflammatory cytokines cause FAT10 upregulation in cancers of liver and colon.53
198514452009High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions.51
164952262006FAT10 plays a role in the regulation of chromosomal stability.31
190333852008The ubiquitin-like modifier FAT10 interacts with HDAC6 and localizes to aggresomes under proteasome inhibition.27
209756832010USE1 is a bispecific conjugating enzyme for ubiquitin and FAT10, which FAT10ylates itself in cis.27

Citation

Joan Oliva ; Samuel W French

UBD (ubiquitin D)

Atlas Genet Cytogenet Oncol Haematol. 2011-11-01

Online version: http://atlasgeneticsoncology.org/gene/43742/ubd