The
Function of Ubiquitin Protein Ligase E3A and its Roles in Human Diseases
Xiaofang
Zhou, Naser Jafari, Shishan Deng, Cai Huang
Xiaofang Zhou,
Shishan Deng, Department of
Anatomy, North Sichuan Medical College, Nanchong, China
Naser Jafari,
Shishan Deng, Cai Huang, Markey
Cancer Center, University of Kentucky, Lexington, KY, USA
Cai Huang, Department of Pharmacology and Nutritional Sciences,
University of Kentucky, Lexington, KY, USA
Correspondence to: Cai Huang, Markey Cancer
Center, University of Kentucky, Lexington, KY 40506, USA
Email: Cai-huang@uky.edu
Telephone: +1- 859-323-9577
Received: January 8,
2015
Revised: January 23, 2015
Accepted: January 25, 2015
Published online: March 30, 2015
ABSTRACT
UBE3A (ubiquitin
protein ligase E3A), also called as human papillomavirus E6 related protein
(E6-AP), functions as a co-activation factor as well as an E3 ubiquitin ligase.
Recent studies show that it plays important roles in the pathogenesis of
genetic diseases, infectious diseases, cardiomyopathy, and cancers. Here, we
reviewed the structure and function of UBE3A and its relation with human
diseases.
© 2015 ACT. All
rights reserved.
Key words: UBE3A; Ubiquitin; Ubiquitination; Human diseases
Zhou XF, Jafari N, Deng SS, Huang C. The Function of
Ubiquitin Protein Ligase E3A and its Roles in Human Diseases. Journal of Biochemistry and Molecular Biology Research 2015; 1(1): 14-18
Available from: URL: http://www.ghrnet.org/index.php/jbmbr/article/view/1011
INTRODUCTION
UBE3A (ubiquitin protein ligase E3A), which was also named human
papillomavirus E6 related protein (E6-AP), is one of the important members in
the ubiquitin proteasome system. The UBE3A gene is located on chromosome 15,
encoding a 100 kDa protein[1].
The protein UBE3A exists in both the nucleus and cytoplasm. It was
detected in many normal human tissues or organs, including prostate, testicles,
ovaries, uterus, breast, and brain tissue[2,3]. UBE3A plays an
important role in the biological function of normal cells as well as the
development of many human diseases. In this review, we summarize the structure
and function of UBE3A and its relation to human diseases.
The
characters of UBE3A gene
UBE3A gene is located on chromosome 15qll-13 in human being, while it is on
chromosome 7 in mice[1,3]. UBE3A coding area is about 60 kb,
and the length of mRNA is about 5 kb. As a result of alternative splicing,
there are several different UBE3A transcripts in cells, and these
transcripts encode different proteins. So far, three different UBE3A protein
isoforms have been identified. They were named as isoform I, II and III,
respectively, and the isoform I is also called as E6-AP. Compared to isoform I,
the isoform II and III have 20 and 23 additional amino acids in their
N-terminus, respectively. These additional N-terminal amino acids are not
essential for the functions of UBE3A. Thus, these different isoforms should
possess the same functions[1].
It was reported that
there are two UBE3A-homologous pseudogenes, UBE3AP1 and UBE3AP2 in cells. The
nucleotide sequences of these genes are 90-95% identical with that of
UBE3A. UBE3AP1 and UBF3AP2 are
located on human chromosome 2 and 21 respectively, and their functions remain
to be understood[4].
The functions of UBE3A protein
UBE3A/E6-AP is composed of 865 amino acid residues, with apparent
molecular weight about 100 kDa. UBE3A/E6-AP protein has five functional
domains, including a HETC domain, an E6 binding domain, a P53 binding domain,
three nuclear receptor response domains and an activation domain[5-7].
In eukaryotic cells, UBE3A/E6-AP has two functions: hormone-dependent
co-activation and ubiquitin protein ligase. The two functions of UBE3A are
relatively independent. In another word, its function as a nuclear hormone
receptor activator is disposable for its ubiquitin protein ligase activity[7].
The function of
UBE3A/E6-AP as a co-activation factor
It is reported that UBE3A plays an important role in gonadal
development, sexual maturation and tumorigenesis. UBE3A is an important
co-activator of steroid hormone receptors, such as androgen receptors (AR),
estrogen receptors (ER) and some auxiliary regulatory proteins. UBE3A interacts
with WW domain binding protein 2 and enhances the activation to AR and ER[8].
UBE3A regulates the activation of steroid hormone receptors and enhances the
activity of the hormone-dependent receptors through its activation domain at
the amino acid terminus[7,9].
In prostate
cells, UBE3A regulates PI3K-Akt signaling pathway by co-activation of steroid
hormone receptors, promoting cell growth and proliferation while inhibiting
apoptosis[10]. Although the over-expression of Akt or PI3K does not
result in tumor formation, they play a good supplementary role for carcinogenic
factors associated with tumorigenesis. PI3K or Akt assists tumor growth by
inhibiting apoptosis and enhancing the tolerance ability to low oxygen and
nutrient deficiency. Thus, UBE3A functions as a co-activation factor to
regulate PI3K-Akt signaling pathway, thus participating in tumorigenesis[9].
The functions
of UBE3A as an ubiquitin ligase
UBE3A is an important member of ubiquitin proteasome system (UPS). The
key functions of UBE3A as an ubiquitin ligase is outlined in figure 1. UBE3A
interacts with the E6 protein of the high-risk human papillomaviruses (HPVs).
The E6/UBE3A complex targets p53 in cervical cancer, resulting in
ubiquitination and degradation of p53[11]. It was reported that
abnormal expression of UBE3A was found in a variety of tumors, such as prostate
cancer, cervical cancer and breast cancer[5], but the specific
relationship between the abnormality of UBE3A and the diseases is poorly
understood.
UBE3A is
regulated by its autoubiquitination and degradation, which is in turn governed
by its interaction with the E6 protein[12]. Over-expression of E6 protein in cells
results in a 3-fold decrease in the half-life of E6AP. Also, the half-life of
E6AP is shorter in HPV-positive cervical cancer cells than in HPV-negative
cervical cancer cells. Tamoxifen (Tam), an ER antagonist widely used for
treatment of hormone-responsive breast cancer, promotes UBE3A auto-ubiquitination
and degradation[13]. Tam-mediated E6AP autoubiquitination is
required for Tam-mediated anti-breast cancer effect. It is generally thought
that the ubiquitin ligase activity plays more important role in the biological
function of UBE3A than its co-activation factor activity. For example,
UBE3A-mediated ubiquitination and degradation of progesterone receptors (PR-B)
is involved in the development of the normal mammary gland; Dysregulation of
UBE3A leads to the occurrence and development of breast tumor[8].
Thus, E6AP is a potential therapeutic target in breast cancer.
A large number
of proteins, including BAK (Bcl-2 homologous antagonist killer), c-MYC, Mcm-7
(minichromosome maintenance protein 7), PR-B (progesterone receptor-B protein),
were found to be substrates of UBE3A[14-18]. Ubiquitination of these
substrates by UBE3A results in their degradation by the UPS. In recent years,
some new substrates of UBE3A were identified, including p27, annexins I, IL - β1
and SOX9.
P27, an
important cell cycle protein kinase inhibitor, plays a crucial role in the
regulation of mammalian cell cycle progression[19]. Carrano etc.
found that UBE3A interacted with p27 through its C-terminal end and caused p27
ubiquitination, resulting in the p27 degradation by the UPS in cells[20].
Depletion of UBE3A by shRNA led to an increase in the level of p27, whereas
over-expression of UBE3A resulted in depression of p27. These results indicate
that UBE3A mediates p27 ubiquitination and degradation[21].
Annexin A1, a
member of annexin family, is associated with the cellular immune response, cell
signaling transmission, cell differentiation, cell proliferation and apoptosis,
and even tumorigenesis[22,23]. It was reported that UBE3A
ubiquitinated annexin A1 by a Ca2+-dependent manner, resulting in
degradation of annexin A1 by the UPS[24]. Annexin A2, another member
of annexin family, is abundantly expressed in many cancer tissues and plays an
important role in tumorigenesis and cancer progression. Annexin A2 was over-expressed
and ubiquitinated in breast cancer tissues[25], and degradation of
annexin A2 is also associated with the UPS in vascular endothelial cells[26].
However, it is unclear whether degradation of annexin A2 is mediated by UBE3A.
Interleukin
1-beta (IL-1β), a cytokine generated by mononuclear-macrophages, plays
important roles in information transmission, activation, proliferation and
differentiation in T and B cells, as well as inflammatory reaction. It was
reported that pro-IL-1β was ubiquitinated and degraded by the UPS in an
E6/E6-AP complex-dependent manner, whereas knockdown of E6-AP restored the
levels of pro-IL-1β. Down-regulation of IL-1 by E6-AP could be a key mechanism
for the immune escape and consequential tumorigenesis of HPV-infected host
cells[27].
Sox9
(SRY-related high mobility group box gene of 9), a gene involved in early
embryonic development, was identified as a testis-determining factor[28].
Sox9 encodes a key transcription factor that regulates cartilage formation,
especially in collagen protein synthesis[29]. It positively
regulated collagen synthesis in the process of development and maturation of
cartilages[30]. It has been shown that Sox9 interacts with the HECT
domain of UBE3A through its HMG domain, and that Sox9 was ubiquitinated in a
UBE3A-dependent manner and consequently degraded by the UPS. Also, the level of
Sox9 in process of cartilage development was regulated by the ubiquitin-protein
ligase function of UBE3A; Abnormal regulation of UBE3A may lead to the occurrence
of cartilage diseases[31].
The roles of UBE3A in human
diseases
Angelman
syndrome
UBE3A is important to maintain the physiological functions of cells[5],
whereas abnormality of UBE3A may contribute to the development of diseases. For
example, the mutation and deletion of maternal UBE3A gene can cause Angelman
syndrome. The patients with Angelman syndrome are characterized as severe
exercise, mental retardation, hypotonia, ataxia, epilepsy, language barriers
and special face with great characteristics of mandible and stick out one's
tongue, which morbidity is about 1/15,000[32]. The animal
experiments showed that topoisomerase inhibitors unsilenced the paternal UBE3A
allele, providing a potential strategy to treat Angelman syndrome.
Prader-Willi
syndrome
Prader-Willi syndrome, similar with Angel syndrome, is a
neurodevelopmental disorder[33]. Prader-Willi syndrome is caused by
defects or mutations of important fragments of paternal chromosome 15. Unlike
Angel’ syndrome, which is caused by the loss of function of UBE3A gene,
Prader-Willi syndrome is considered a contiguous gene disorder. Although
Prader-Willi syndrome is caused by defects in multiple genes, the imprinting of
paternal UBE3A by UBE3A antisense transcript (UBE3A-ATS) is involved in the pathological
process of this disease[34]. UBE3A imprinting by UBE3A-ATS inhibits
the expression of UBE3A in neurons, and UBE3A imprinting in neurons only
requires UBE3A-ATS expression, indicating a role of UBE3A in Prader-Willi
syndrome[35].
Infectious
diseases
E6-AP binds to the substrate binding domain of Hsp70/Hsc70 chaperones
and enhances the degradation of chaperone bound proteins[36].
Stresses induce a dramatical increase in the expression of E6-AP, while
overexpression of E6-AP protects against endoplasmic reticulum stress-induced
cell death. Furthermore, UBE3A was redistributed in microtubule, resulting in
inhibition of apoptosis induced by stress. Interestingly, hepatitis c virus
(HCV) infection induces UBE3A-mediated ubiquitination and degradation of target
proteins, such as HCV core protein. HCV core protein plays an important role in
tumorigenesis and progress of liver cancer related with HCV[37-40].
Cardiomyopathy
Cardiomyopathy, a progressive disease, results from changes of
ventricular structure and impairing of cardiac function, which leads to a high
mortality. However, the underlying mechanisms of cardiomyopathy remain to be
elucidated. Some evidence suggests that cardiomyopathies might be involved in
cell apoptosis. It is reported that the transcriptional and translational
levels of both UBE3A and p53 significantly increase in response to H2O2
treatment. This result suggests a potential role of UBE3A and p53 in myocardial
cell apoptosis[39].
UBE3A
plays an important role in cancers
Cervical cancer
UBE3A is tightly related with tumors. It has been shown that expression
of UBE3A increases in cervical cancer tissues, and the level of UBE3A
positively correlates with the malignant phenotypes of cervical cancer. Knock
down of UBE3A results in suppression in the proliferation of cervical cancer
cells while promotion of apoptosis[40]. Also, p53 was accumulated in
HPV-positive cervical cancer cells upon UBE3A knockdown, accompanying with
growth inhibition of both HeLa and SiHa lines. These results indicated that
high level of UBE3A in cervical cancer cells might trigger tumor progression[41].
It has been reported that GRIM-19, a cell death regulatory protein, prevent
E6/E6-AP complexes from degrading p53, resulting in the accumulation of p53 and
consequently promoting apoptosis of cancer cells[42]. Thus, E6-AP
might be a potential therapeutic molecular target in cervical intraepithelial
neoplasia[43].
Prostate cancer
Transfection of LnCap
prostate cancer cells with plasmid expressing E6-AP by electroporation promoted
the abilities of migration and invasion of prostate cancer cells, indicating
the role of E6-AP in the invasion and migration of prostate cancer cells.
Over-expression of UBE3A also strengthened the proliferation of prostate cancer
cells with more cells in S phase, and enhanced the size of prostate cancer
cells[10]. In prostate cancer tissues, the level of UBE3A is
negatively correlated with those of androgen receptors (AR). Also, the
interaction of UBE3A with AR and the increase in AR protein level in the
prostate glands of UBE3A null mice suggest the role of UBE3A in regulating AR
degradation[44].
Breast cancer
It is well known that UBE3A regulates a variety of biological process,
such as transcription, signal transduction, cell survival, cell cycle control,
and DNA repair[45]. We have showed that the expression levels of
UBE3A in breast cancer tissue samples are 2-fold higher than those in the
adjacent normal tissues, as determined by restriction fragment differential
display polymerase chain reaction (RFDD-PCR) and matrix-assisted laser
desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF-TOF
MS) combined with two-dimensional polyacrylamide gel electrophoresis. UBE3A was
differently expressed in human breast cancer tissues, which was expressed in
root distribution-like breast cancer cells more than nest-like cancer cells[46].
Ramamoorthy et al. also confirmed that abnormal expression of UBE3A could lead
to occurrence of breast cancer[47]. Furthermore, the level of UBE3A
negatively correlates with the expression of ER in breast cancer tissues,
probably because of the ubiquitination of ER by UBE3A. Tamoxifen treatment
reduced expression level of UBE3A, while enhanced that of some relevant factors
with UBE3A, including cytochrome c, Bax and p21, suggesting that UBE3A could be
one of therapeutic targets for breast cancers[45].
Conclusions
UBE3A regulates cell proliferation, apoptosis, immune
escape and the development of breast and cartilage through ubiquitinating a
variety of substrate proteins, such as p53, p27, BAK, pro-IL-1, PR-B and Sox9,
as well as its function as a steroid hormone receptor coactivation factor. Initially, it was found to be related
with cervical cancer involved in HPV, but more and more evidence show that it
is associated with many human diseases, including Angel's syndrome,
Prader-Willi syndrome, infectious diseases, cardiomyopathy, cervical cancer,
prostate cancer and breast cancer. UBE3A could be a potential therapeutic
target for some diseases, such as cancers. However, detailed molecular
mechanisms and its precise roles in human diseases remain to be defined.
Acknowledgements
This work is supported by an American Cancer Society
Research Scholar Grant (RSG-13-184-01-CSM), and a start-up fund from Markey
Cancer Center, University of Kentucky (to C.H.). S.D. is a visiting scholar
from North Sichuan Medical College supported by China Scholarship council.
CONFLICT OF INTERESTS
The Author has no conflicts of interest to declare.
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Peer reviewer: Junsoo Park, Ph.D,
Professor, Division of Biological Science and Technology, Yonsei University, 1
Yonseidaegil, Wonju city, Kangwon Province, 220-710, Korea (ROK).
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