UBE2C (ubiquitin-conjugating enzyme E2C)

2008-06-01 Pierlorenzo Pallante , Maria Teresa Berlingieri , Alfredo Fusco Affiliation

Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c\\\/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facolta di Medicina e Chirurgia, Universita degli Studi di Napoli Federico II, via Pansini 5, 80131 Napoli, Italy

Identity

HGNC

UBE2C

LOCATION

20q13.12

LOCUSID

11065

ALIAS

UBCH10,dJ447F3.2

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

UBE2C is located on chromosome 20, at 20q13.12 according to Entrez Gene. In AceView, it covers 4.40 kb, from 43874623 to 43879017 on the direct strand.

Transcription

There are 6 representative transcripts annotated in RefSeq database, but, according to AceView, Homo sapiens cDNA sequences in GenBank support at least 13 spliced variants. Isoform 1, the longest isoform, is composed of 6 coding exons of varying lengths, separated by introns: NM_007019.2 (mRNA-ubiquitin-conjugating enzyme E2C): mRNA product length: 823.

Proteins

Description

The UbcH10 gene encodes a member of the E2 ubiquitin-conjugating enzyme family that is involved in the ubiquitin dependent proteolysis. In this pathway, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), together with ubiquitin ligase (E3), catalyze the covalent attachment of ubiquitin to target proteins, targeting them for degradation mediated by the 26S proteasome.
The full-length UbcH10 contains 179 residues for a 19.6 kDa weight. It belongs to the class III Ubc proteins that are characterized by an NH2-terminal extension followed by the "core" Ubc fold.
Like all E2 enzymes, UbcH10 contains an active site cysteine residue (position 114) that is crucial for the formation of the ubiquitin-thiolester. Alteration of this residue C(114)S strongly inhibits ubiquitination of cyclin A and Cyclin B confering a dominant-negative phenotype.
Levels of UbcH10 are modulated by autoubiquitination. This process is dependent on a motif, the "destruction box" [Arg-X-X-Leu-X-X-(Leu/Ile)-X-Asp] recognized by the mitotic-specific ubiquitination machinery.
A study suggests that a destruction box is present in the UbcH10 sequence and includes residues 129-132 (Arg-Thr-Ile-Leu). Interestingly an SNP is reported for the residue 129 (refSNP ID: rs7352110, alleles A/G, Arg>Gly).
This would be important since any change in the putative destruction box could stabilize UbcH10 against destruction.

Expression

UbcH10 mRNA and protein are expressed at low levels in most adult normal tissues. In contrast, UbcH10 mRNA and protein are highly expressed in tumor tissues. Moreover, UbcH10 protein levels fluctuate during the cell cycle being abundant during M and early G1 phases, but decreasing in late G1, S and G2 phases.

Localisation

Nucleoplasm.
Cytosol.

Function

UbcH10 is crucial for cell cycle progression during the G2/M phase, since its function is required for the destruction of mitotic cyclins and other mitosis-related substrates. UbcH10 interacts with the multiprotein complex APC (anaphase-promoting complex), which has E3 ubiquitin ligase activity, and targets for destruction substrates from the preceding mitosis (cyclin A, cyclin B, securin, geminin). Once these target proteins have been degraded, UbcH10 adds ubiquitins to itself, triggering its own destruction. As a result, the absence of UbcH10 allows the accumulation of cyclin A, which in turn contributes to the APC inactivation, providing a molecular switch that allows cells to proceed from cell division to a new round of DNA duplication. Hence, the function of UbcH10 is strictly linked to the progression of cell cycle through the M phase and the coupling of mitosis to S-phase entry via autonomous regulation of the anaphase-promoting complex.

Implicated in

Entity name

Human cancers

Note

Several studies suggest a possible use of UbcH10 investigation (together with other molecular markers) in early detection of cancer. Other studies suggest that inhibition of UbcH10 could have a therapeutic potential in cancer treatment.

Disease

UbcH10 overexpression was reported in a number of human cancer cell lines and primary tumors and expression data strongly support an association between high UbcH10 expression and a poor tumor differentiation. Expression studies have also shown a correlation between UbcH10 overexpression and the proliferation status since there is a good association with the proliferation marker Ki-67/MIB1. It was found overexpressed in lung carcinoma ( squamous and adenocarcinoma, poorly versus well differentiated), bladder carcinoma (grade 3 versus grade 2), prostate carcinoma(metastatic versus primary), gastric adenocarcinoma cervical, esophageal adenocarcinoma(adenocarcinoma versus Barretts metaplasia), breast cancer (grade 3 versus grade 1, malignant versus benign neoplastic lesions), brain ( astrocytomas versus low-grade tumors or normal controls), medulloblastoma, ovarian carcinoma (grade 3 versus grade 1 and 2), thyroid carcinoma (poorly versus well differentiated), adrenocortical gland, Wilms tumor (relapsed versus relapse-free) hepatocellular carcinoma (correlation with higher frequencies of invasion to capsular formation, invasion to portal vein and tumor de-differentiation). Several expression analysis and functional studies have also shown that UbcH10 resulted up-regulated in experimental model of carcinogenesis, that its overexpression lead to the acquisition of a malignant phenotype and that its knockdown successfully resulted in growth arrest.

Prognosis

It was seen that UbcH10 overexpression is a negative predictor of clinical outcome in patients affected by ovarian and hepatocellular carcinoma. Therefore, UbcH10 has been suggested as an helpful prognostic indicator for ovarian and hepatocellular carcinoma patients.

Oncogenesis

20q13.1 chromosomal region is frequently associated with genomic amplification in different malignant neoplasias and amplification of UbcH10 locus has been reported in the case of gastroesophageal carcinomas, colorectal carcinomas with liver metastases, cervical cancers, ovarian carcinomas, gliomas and culture cell lines obtained from anaplastic thyroid carcinomas.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
17933517	2007	UbcH10 is overexpressed in malignant breast carcinomas.	Berlingieri MT et al
16204036	2005	Functional network analysis reveals extended gliomagenesis pathway maps and three novel MYC-interacting genes in human gliomas.	Bredel M et al
17659439	2008	Prediction of metastatic relapse in node-positive breast cancer: establishment of a clinicogenomic model after FEC100 adjuvant regimen.	Campone M et al
17220641	2006	Combination of multiple mRNA markers (PTTG1, Survivin, UbcH10 and TK1) in the diagnosis of Taiwanese patients with breast cancer by membrane array.	Chen CC et al
12427990	2002	Molecular characterization of plant ubiquitin-conjugating enzymes belonging to the UbcP4/E2-C/UBCx/UbcH10 gene family.	Criqui MC et al
15260889	2004	A molecular 'signature' of primary breast cancer cultures; patterns resembling tumor tissue.	Dairkee SH et al
17354233	2007	Identification of overexpressed genes in hepatocellular carcinoma, with special reference to ubiquitin-conjugating enzyme E2C gene expression.	Ieta K et al
15949568	2005	In silico chromosomal clustering of genes displaying altered expression patterns in ovarian cancer.	Israeli O et al
18331723	2008	Expression of ubiquitin-conjugating enzyme E2C/UbcH10 in astrocytic tumors.	Jiang L et al
15749827	2005	A novel UbcH10-binding protein facilitates the ubiquitinylation of cyclin B in vitro.	Kobirumaki F et al
17465858	2007	Molecular cytogenetic profiles of novel and established human anaplastic thyroid carcinoma models.	Lee JJ et al
17217624	2006	Expression and effect of inhibition of the ubiquitin-conjugating enzyme E2C on esophageal adenocarcinoma.	Lin J et al
11927573	2002	Structural and functional analysis of the human mitotic-specific ubiquitin-conjugating enzyme, UbcH10.	Lin Y et al
17243165	2007	Gene dosage alterations revealed by cDNA microarray analysis in cervical cancer: identification of candidate amplified and overexpressed genes.	Narayan G et al
12874022	2003	UbcH10 is the cancer-related E2 ubiquitin-conjugating enzyme.	Okamoto Y et al
16106252	2005	UbcH10 overexpression may represent a marker of anaplastic thyroid carcinomas.	Pallante P et al
16896351	2006	The anaphase promoting complex/cyclosome: a machine designed to destroy.	Peters JM et al
15558010	2004	Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry.	Rape M et al
16413484	2006	The processivity of multiubiquitination by the APC determines the order of substrate degradation.	Rape M et al
17443186	2007	Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation.	Reddy SK et al
17443180	2007	Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities.	Stegmeier F et al
16772118	2006	Detection of aberrations of ubiquitin-conjugating enzyme E2C gene (UBE2C) in advanced colon cancer with liver metastases by DNA microarray and two-color FISH.	Takahashi Y et al
11739784	2001	APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex.	Tang Z et al
9122200	1997	Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase.	Townsley FM et al
15208666	2004	Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin.	Wagner KW et al
17624412	2007	Estrogen-regulated gene expression predicts response to endocrine therapy in patients with ovarian cancer.	Walker G et al
8723350	1996	Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation.	Yu H et al
16287080	2006	Expression profiling of Wilms tumors reveals new candidate genes for different clinical parameters.	Zirn B et al
16969093	2006	Before and after the spindle assembly checkpoint--an APC/C point of view.	de Gramont A et al

Other Information

Locus ID:

NCBI: 11065
MIM: 605574
HGNC: 15937
Ensembl: ENSG00000175063

Variants:

dbSNP: 11065
ClinVar: 11065
TCGA: ENSG00000175063
COSMIC: UBE2C

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000175063	ENST00000243893	K4DI81
ENSG00000175063	ENST00000335046	O00762
ENSG00000175063	ENST00000352551	O00762
ENSG00000175063	ENST00000356455	O00762
ENSG00000175063	ENST00000356455	Q5TZN3
ENSG00000175063	ENST00000372568	O00762
ENSG00000175063	ENST00000405520	A0A0A0MSE8
ENSG00000175063	ENST00000617055	A0A087WVK1

Expression (GTEx)

100

150

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Ubiquitin mediated proteolysis	KEGG	ko04120
Ubiquitin mediated proteolysis	KEGG	hsa04120
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Immune System	REACTOME	R-HSA-168256
Adaptive Immune System	REACTOME	R-HSA-1280218
Class I MHC mediated antigen processing & presentation	REACTOME	R-HSA-983169
Antigen processing: Ubiquitination & Proteasome degradation	REACTOME	R-HSA-983168
Cell Cycle	REACTOME	R-HSA-1640170
Cell Cycle Checkpoints	REACTOME	R-HSA-69620
Mitotic Spindle Checkpoint	REACTOME	R-HSA-69618
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	REACTOME	R-HSA-141405
Inactivation of APC/C via direct inhibition of the APC/C complex	REACTOME	R-HSA-141430
Cell Cycle, Mitotic	REACTOME	R-HSA-69278
M Phase	REACTOME	R-HSA-68886
Mitotic Metaphase and Anaphase	REACTOME	R-HSA-2555396
Mitotic Anaphase	REACTOME	R-HSA-68882
Separation of Sister Chromatids	REACTOME	R-HSA-2467813
Regulation of mitotic cell cycle	REACTOME	R-HSA-453276
APC/C-mediated degradation of cell cycle proteins	REACTOME	R-HSA-174143
Regulation of APC/C activators between G1/S and early anaphase	REACTOME	R-HSA-176408
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	REACTOME	R-HSA-176814
Phosphorylation of the APC/C	REACTOME	R-HSA-176412
APC/C:Cdc20 mediated degradation of mitotic proteins	REACTOME	R-HSA-176409
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	REACTOME	R-HSA-179419
Cdc20:Phospho-APC/C mediated degradation of Cyclin A	REACTOME	R-HSA-174184
APC-Cdc20 mediated degradation of Nek2A	REACTOME	R-HSA-179409
APC/C:Cdc20 mediated degradation of Cyclin B	REACTOME	R-HSA-174048
APC/C:Cdc20 mediated degradation of Securin	REACTOME	R-HSA-174154
Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase	REACTOME	R-HSA-176407
APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	REACTOME	R-HSA-174178
Autodegradation of Cdh1 by Cdh1:APC/C	REACTOME	R-HSA-174084
Cellular responses to stress	REACTOME	R-HSA-2262752
Cellular Senescence	REACTOME	R-HSA-2559583
Senescence-Associated Secretory Phenotype (SASP)	REACTOME	R-HSA-2559582
Protein ubiquitination	REACTOME	R-HSA-8852135
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	REACTOME	R-HSA-8866652

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38637730	2024	UBE2C promotes the proliferation of acute myeloid leukemia cells through PI3K/AKT activation.	0
38949026	2024	UBE2C-induced crosstalk between mono- and polyubiquitination of SNAT2 promotes lymphatic metastasis in bladder cancer.	0
38637730	2024	UBE2C promotes the proliferation of acute myeloid leukemia cells through PI3K/AKT activation.	0
38949026	2024	UBE2C-induced crosstalk between mono- and polyubiquitination of SNAT2 promotes lymphatic metastasis in bladder cancer.	0
36548081	2023	The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells.	12
37168048	2023	Expression significance of Emi1, UBCH10 and CyclinB1 in esophageal squamous cell carcinoma.	1
37335710	2023	Aberrant expression of UBE2C in endometrial cancer and its correlation to epithelial mesenchymal transition.	1
37486389	2023	Restored UBE2C expression in islets promotes β-cell regeneration in mice by ubiquitinating PER1.	1
37496990	2023	FOXM1-regulated ZIC2 promotes the malignant phenotype of renal clear cell carcinoma by activating UBE2C/mTOR signaling pathway.	1
37535572	2023	System analysis identifies UBE2C as a novel oncogene target for adrenocortical carcinoma.	2
37580802	2023	Comprehensive analysis of UBE2C expression and its potential roles and mechanisms in hepatocellular carcinoma.	1
37848988	2023	Identification of transcriptome characteristics of granulosa cells and the possible role of UBE2C in the pathogenesis of premature ovarian insufficiency.	1
37958776	2023	Role of UBE2C in Brain Cancer Invasion and Dissemination.	3
38009019	2023	UBE2C promotes malignancy of cutaneous squamous cell carcinoma.	0
38102624	2023	Ubiquitin-conjugating enzyme E2C (UBE2C) is a prognostic indicator for cholangiocarcinoma.	0

Citation

Pierlorenzo Pallante ; Maria Teresa Berlingieri ; Alfredo Fusco

UBE2C (ubiquitin-conjugating enzyme E2C)

Atlas Genet Cytogenet Oncol Haematol. 2008-06-01

Online version: http://atlasgeneticsoncology.org/gene/44079