Human RING finger protein ZNF645 is a novel testis-specific E3 ubiquitin ligase

A large number of testis-specific genes are involved in the complex process of mammalian spermatogenesis. Identification of these genes and their roles is important for understanding the mechanisms underlying spermatogenesis. Here we report on a novel human RING finger protein, ZNF645, which contains a C3HC4 RING finger domain, a C2H2 zinc-finger domain, and a proline-rich region, indicating that it has a structure similar to that of the c-Cbl-like protein Hakai. ZNF645 was exclusively expressed in normal human testicular tissue. Immunohistochemical analysis confirmed that ZNF645 protein was present in spermatocytes, round and elongated spermatids, and Leydig cells. Immunofluorescence staining of mature sperms further showed that the ZNF645 protein was localized over the postacrosomal perinuclear theca region and the entire length of sperm tail. An in vitro ubiquitination assay indicated that the RING finger domain of the ZNF645 protein had E3 ubiquitin ligase activity. Therefore, we suggest that ZNF645 might act as an E3 ubiquitin-protein ligase and play a role in human sperm production and quality control.

Molecular cloning and functional characterization of apple U-box E3 ubiquitin ligase gene MdPUB29 reveals its involvement in salt tolerance

An E3 ubiquitin ligase gene(Genbank accession no.:MD01 G1010900) was cloned from the Royal Gala apple genome(Malus×domestica Borkh.).Sequence analysis showed that the length of the MdPUB29 gene was 1 275 bp,encoding 424 amino acids.Phylogenetic tree analysis indicated that the apple E3 ubiquitin ligase exhibited the greatest sequence similarity to Pyrus×bretschneideri.The predicted protein structural domain of MdPUB29 showed that it contained a U-box domain.qRT-PCR analysis showed that Md PUB29 was expressed widely in different tissues of the Royal Gala apple species,and was highly expressed in the root,while the expression of MdPUB29 was significantly inhibited by exogenous NaCl.Immunoblotting assays revealed that MdPUB29 protein abundance in tissue cultures of the Royal Gala apple accumulated under NaC l stress conditions.Three-dimensional protein structure prediction indicated that MdPUB29 was highly homologous with AtPUB29.The growing potential of MdPUB29-expressing apple calli and Arabidopsis were much stronger than that of the control under salt stress conditions,suggesting that MdPUB29 may positively regulate salt tolerance.

Role of E3 ubiquitin ligases in lung cancer

E3 ubiquitin ligases are a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome.Therefore,E3 ubiquitin ligases play an essential role in a variety of biological processes including cell cycle regulation,proliferation and apoptosis.E3 ubiquitin ligases are often found overexpressed in human cancers,including lung cancer,and their deregulation has been shown to contribute to cancer development.However,the lack of specific inhibitors in clinical trials is a major issue in targeting E3 ubiquitin ligases with currently only one E3 ubiquitin ligase inhibitor being tested in the clinical setting.In this review,we focus on E3 ubiquitin ligases that have been found deregulated in lung cancer.Furthermore,we discuss the processes in which they are involved and evaluate them as potential anti-cancer targets.By better understanding the mechanisms by which E3 ubiquitin ligases regulate biological processes and their exact role in carcinogenesis,we can improve the development of specific E3 ubiquitin ligase inhibitors and pave the way for novel treatment strategies for cancer patients.

Role of E3 ubiquitin ligases in gastric cancer

E3 ubiquitin ligases have an important role in carcinogenesis and include a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome.So far,E3 ubiquitin ligases have been reported to have a role in a variety of biological processes including cell cycle regulation,cell proliferation,and apoptosis.Recently,several kinds of E3 ubiquitin ligases were demonstrated to be generally highly expressed in gastric cancer(GC) tissues and to contribute to carcinogenesis.In this review,we summarize thecurrent knowledge and information about the clinical significance of E3 ubiquitin ligases in GC.Bortezomib,a proteasome inhibitor,encouraged the evaluation of other components of the ubiquitin proteasome system for pharmaceutical intervention.The clinical value of novel treatment strategies targeting aberrant E3 ubiquitin ligases for GC are discussed in the review.

微小核糖核酸-1205沉默Cullin-RING泛素E3连接酶4A激活AMPK信号传导保护人成骨细胞免受地塞米松损伤的研究

目的:腺苷酸活化蛋白激酶(AMPK)激活可以抑制地塞米松(Dex)诱导的成骨细胞损伤。Cullin-RING泛素E3连接酶4A(CUL4A)决定了AMPKα泛素化和蛋白酶体降解。本研究鉴定了一种新型的靶向CUL4A的微小核糖核酸-1205(miR-1205)。方法:为了研究miR-1205对Dex诱导人类成骨细胞的氧化损伤和细胞死亡的影响,对hFOB1.19成骨细胞和原代人成骨细胞进行培养和分化,提取第3~10代的原始人类成骨细胞总细胞RNA,并通过反转录获得c DNA。利用qPCR、2ΔΔCt方法进行数据定量,分析miR-1205的表达。将生成表达premiR-1205的慢病毒(lv-premiR-1205)或miR-1205反义慢病毒(lv-antagomiR-1205),进行过滤并添加至h FOB1.19细胞或人成骨细胞。将细胞接种到六孔板中,通过miR模拟物转染,进行遗传修饰。检查CUL4A 3’-UTR荧光素酶的活性,并对结果进行量化。在对hFOB1.19细胞使用Dex处理后,对细胞功能包括细胞生存力测定,细胞死亡检测,以及通过核TUNEL染色和caspase-3活性测定及Western印迹测定进行细胞凋亡检查。结果:将CUL4A七个靶向miRNA模拟物中的每一个都分别转染到hFOB1.19成骨细胞中。其中,miR-1205模拟物导致最显著的CUL4A mRNA降低。miR-1205的亚细胞分布表明,内源性miR-1205的大部分位于细胞质中。生物素化的miR-1205与hFOB1.19细胞中的CUL4A m RNA直接关联并使其沉默,从而导致AMPK级联激活,并显著减弱h FOB1.19细胞中Dex诱导的细胞毒性。此外,miR-1205的过表达显著抑制了hFOB1.19细胞中Dex诱导的凋亡激活。结论:在h FOB1.19细胞和人类成骨细胞中,通过miR-1205沉默CUL4A,激活了AMPK信号传导,并调节其下游靶标发挥有效的抗氧化活性,极大减弱Dex诱导的细胞毒性,从而显著保护成骨细胞。

Research Progress in Function and Regulation of E3 Ubiquitin Ligase SMURF1

Smad ubiquitylation regulatory factor 1(Smurf1)is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase.Initially,Smurf1 was reportedly involved in the negative regulation of the bone morphogenesis protein(BMP)pathway.After further research,several studies have confirmed that Smurf1 is widely involved in various biological processes,such as bone homeostasis regulation,cell migration,apoptosis,and planar cell polarity.At the same time,recent studies have provided a deeper understanding of the regulatory mechanisms of Smurf1’s expression,activity,and substrate selectivity.In our review,a brief summary of recent important biological functions and regulatory mechanisms of E3 ubiquitin ligase Smurf1 is proposed.

The E3 ubiquitin ligase seven in absentia homolog 1 may be a potential new therapeutic target for Parkinson's disease

In this study, we investigated the effect of an antibody against E3 ubiquitin ligase seven in absentia homolog 1（SIAH-1） in PC12 cells. 1-Methyl-4-phenylpyridinium（MPP＋） treatment increased α-synuclein, E1 and SIAH-1 protein levels in PC12 cells, and it reduced cell viability; however, there was no significant change in light chain 3 expression. Treatment with an SIAH-1 antibody decreased m RNA expression levels of α-synuclein, light chain 3 and SIAH-1, but increased E1 m RNA expression. It also increased cell viability. Combined treatment with MPP＋ and rapamycin reduced SIAH-1 and α-synuclein levels. Treatment with SIAH-1 antibody alone diminished α-synuclein immunoreactivity in PC12 cells, and reduced the colocalization of α-synuclein and light chain 3. These findings suggest that the SIAH-1 antibody reduces the monoubiquitination and aggregation of α-synuclein, promoting its degradation by the ubiquitin-proteasome pathway. Consequently, SIAH-1 may be a potential new therapeutic target for Parkinson’s disease.

Jianpi Decoction Combined with Medroxyprogesterone Acetate Alleviates Cancer Cachexia and Prevents Muscle Atrophy by Directly Inhibiting E3 Ubiquitin Ligase

ObjectiveTo provide comprehensive evidence for the anti-cancer cachexia effect of Jianpi Decoction(JP)and to explore its mechanism of anti-cancer cachexia.MethodsA mouse model of colon cancer(CT26)-induced cancer cachexia(CC)was used to investigate the anti-CC effect of JP combined with medroxyprogesterone acetate(MPA).Thirty-six mice were equally divided into 6 groups:normal control,CC,MPA(100 mg·kg^(−1)·d^(−1)),MPA+low-dose(20 mg·kg^(−1)·d^(−1))JP(L-JP),MPA+medium-dose(30 mg·kg^(−1)·d^(−1))JP(M-JP),and MPA+high-dose(40 mg·kg^(−1)·d^(−1))JP(H-JP)groups.After successful modeling,the mice were administered by gavage for 11 d.The body weight and tumor volume were measured and recorded every 2 d starting on the 8th day after implantation.The liver,heart,spleen,lung,kidney,tumor and gastrocnemius muscle of mice were collected and weighed.The pathological changes of the tumor was observed,and the cross-sectional area of the gastrocnemius muscle was calculated.The protein expressions of STAT3 and E3 ubiquitinase in the gastrocnemius muscle were measured by Western blot.In addition,an in vitro C2C12 myotube formation model was established to investigate the role of JP in hindering dexamethasone-induced muscle atrophy.In vitro experiments were divided into control,model,and JP serum groups.After 2-d administration,microscopic photographs were taken and myotube diameters were calculated.Western blot was performed to measure the protein expressions of STAT3 and E3 ubiquitinase.ResultsJP combined with MPA restored tumor-induced weight loss(P<0.05,vs.CC)and muscle fiber size(P<0.01,vs.CC).Mechanistically,JP reduced the expression of atrophy-related proteins MuRF1 and MAFbx in tumor-induced muscle atrophy in vivo(P<0.05,vs.CC).In addition,JP reduced the expression of atrophy-related proteins MuRF1 and MAFbx and p-STAT3 phosphorylation(P<0.05 or P<0.01 vs.model group)in C2C12 myotubes treated with dexamethasone in vitro.ConclusionsAdministration of JP combined with MPA restores tumor-induced cachexia conditions.In addition,the profound effect of JP combined with MPA on tumor-induced cachexia may be due to its inhibition of muscle proteolysis(E3 ubiquitinase system).

Dynamic modulation of nodulation factor receptor levels by phosphorylation-mediated functional switch of a RING-type E3 ligase during legume nodulation

The precise control of receptor levels is crucial for initiating cellular signaling transduction in response to specific ligands;however,such mechanisms regulating nodulation factor(NF)receptor(NFR)-mediated perception of NFs to establish symbiosis remain unclear.In this study,we unveil the pivotal role of the NFR-interacting RING-type E3 ligase 1(NIRE1)in regulating NFR1/NFR5 homeostasis to optimize rhizobial infection and nodule development in Lotus japonicus.We demonstrated that NiRE1 has a dual function in this regulatory process.It associates with both NFR1 and NFR5,facilitating their degradation through K48-linked polyubiquitination before rhizobial inoculation.However,following rhizobial inoculation,NFR1 phosphorylates NIRE1ata conserved residue,Tyr-109,inducing a functional switch in NIRE1,which enables NIRE1tomediateK63-linkedpolyubiquitination,thereby stabilizing NFR1/NFR5 in infected root cells.The introduction of phospho-dead NIRE1Y1osF leads to delayed nodule development,underscoring the significance of phosphorylation at Tyr-1o9 in orchestrating symbiotic processes.Conversely,expression of the phospho-mimic NIRE1Y0E results in the formation of spontaneous nodules in L.japonicus,further emphasizing the critical role of the phosphorylation-dependent functional switch in NiRE1.In summary,these findings uncover a fine-tuned symbiotic mechanism that a single E3 ligase could undergo a phosphorylationdependent functional switch to dynamically and precisely regulate NF receptor protein levels.

Expression Pattern, Interaction Network, and Functional Analysis of the Arabidopsis Botrytis Susceptible1 Interactor

E3 ubiquitin ligases are participated in numerous processes, regulating the response to biotic and abiotic stresses. Botrytis susceptible1 interactor (BOI) is a RING (Really Interesting New Gene)-type E3 ligase that mediates the ubiquitination of BOS1 (Botrytis susceptible1), a transcription factor involved in stress and pathogen responses. Although BOI is an E3 ligase, there are reports to show that BOI interacts with target proteins such as DELLAs or CONSTANS to repress gibberellin responses and flowering without the degradation of the target proteins. In this article, we utilize diversified methods to comprehensively analyze the expression pattern, interaction network and function of BOI gene. Firstly, 1800 bp upstream region of BOI gene from Arabidopsis thaliana (Arabidopsis) genome was isolated, and fused GUS reporter gene. The resulting expression cassette was introduced into wild-type Arabidopsis through Agrobacterium-mediated transformation. The result demonstrated that BOI gene was expressed predominantly in leaves, siliques, young roots, and flowering tissues, indicating that BOI gene may be involved in multiple processes in plant growth and development in Arabidopsis. Besides, eight candidate interacting proteins were obtained from the Arabidopsis cDNA library via yeast two-hybrid technology, including EXO70E2 (AT5G61010), WRKY7 (AT4G24240), WRKY11 (AT4G31550), WRKY17 (AT2G24570), UBP20 (AT4G17895), L5 (AT1G12290), SAUR9 (AT4G36110) and TCP21 (AT5G08330). Functional analysis of these candidate interacting proteins manifested that they related to multiple pathways, including biological and abiotic stress, programmed cell death, protein degradation, material metabolism and transcriptional regulation. In addition, the results of the transient assay proclaimed that BOI protein affects the protein stability of EXO70E2 and L5 through its E3 ubiquitin ligase activity. Our results provide novel clues for a better understanding of molecular mechanisms underlying BOI-mediated regulations.

Arabidopsis U-box E3 ubiquitin ligase PUB11 negatively regulates drought tolerance by degrading the receptor-like protein kinases LRR1 and KIN7

Both plant receptor-like protein kinases(RLKs)and ubiquitin-mediated proteolysis play crucial roles in plant responses to drought stress.However,the mechanism by which E3 ubiquitin ligases modulate RLKs is poorly understood.In this study,we showed that Arabidopsis PLANT U-BOX PROTEIN 11(PUB11),an E3 ubiquitin ligase,negatively regulates abscisic acid(ABA)-mediated drought responses.PUB11 interacts with and ubiquitinates two receptor-like protein kinases,LEUCINE RICH REPEAT PROTEIN 1(LRR1)and KINASE 7(KIN7),and mediates their degradation during plant responses to drought stress in vitro and in vivo.pub11 mutants were more tolerant,whereas Irr1 and kin7 mutants were more sensitive,to drought stress than the wild type.Genetic analyses show that the pub11 Irr1 kin7 triple mutant exhibited similar drought sensitivity as the Irr1 kin7 double mutant,placing PUB11 upstream of the two RLKs.Abscisic acid and drought treatment promoted the accumulation of PUB11,which likely accelerates LRR1 and KIN7 degradation.Together,our results reveal that PUB11 negatively regulates plant responses to drought stress by destabilizing the LRR1 and KIN7 RLKs.

Functional characterization of SAG/RBX2/ROC2/RNF7, an antioxidant protein and an E3 ubiquitin ligase

SAG(Sensitive to Apoptosis Gene),also known as RBX2(RING box protein 2),ROC2(Regulator of Cullins 2),or RNF7(RING Finger Protein 7),was originally cloned in our laboratory as a redox inducible antioxi-dant protein and later characterized as the second member of the RBX/ROC RING component of the SCF(SKP1-CUL-F-box Proteins)E3 ubiquitin ligase.When acting alone,SAG scavenges oxygen radicals by forming inter-and intra-molecular disulfide bonds,whereas by forming a complex with other components of the SCF E3 ligase,SAG promotes ubiquitination and degradation of a number of protein substrates,includ-ing c-JUN,DEPTOR,HIF-1α,IκBα,NF1,NOXA,p27,and procaspase-3,thus regulating various signaling path-ways and biological processes.Specifically,SAG pro-tects cells from apoptosis,confers radioresistance,and plays an essential and non-redundant role in mouse embryogenesis and vasculogenesis.Furthermore,stress-inducible SAG is overexpressed in a number of human cancers and SAG overexpression correlates with poor patient prognosis.Finally,SAG transgenic expression in epidermis causes an early stage inhibi-tion,but later stage promotion,of skin tumorigenesis triggered by DMBA/TPA.Given its major role in pro-moting targeted degradation of tumor suppressive proteins,leading to apoptosis suppression and accel-erated tumorigenesis,SAG E3 ligase appears to be an attractive anticancer target.

Role of SKP1-CUL1-F-Box-Protein (SCF) E3 Ubiquitin Ligases in Skin Cancer

Many biological processes such as cell proliferation, differentiation, and cell death depend precisely on the timely synthesis and degradation of key regulatory proteins. While protein synthesis can be regulated at multiple levels, protein degradation is mainly controlled by the ubiquitin-proteasome system （UPS）, which consists of two distinct steps： （1） ubiquitylation of targeted protein by E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase, and （2） subsequent degradation by the 26S proteasome. Among all E3 ubiquitin ligases, the SCF （SKP1-CUL1-F-box protein） E3 ligases are the largest family and are responsible for the turnover of many key regulatory proteins. Aberrant regulation of SCF E3 ligases is associated with various human diseases, such as cancers, including skin cancer. In this review, we provide a comprehensive overview of all currently published data to define a promoting role of SCF E3 ligases in the development of skin cancer. The future directions in this area of research are also discussed with an ultimate goal to develop small molecule inhibitors of SCF E3 ligases as a novel approach for the treatment of human skin cancer. Furthermore, altered components or substrates of SCF E3 ligases may also be developed as the biomarkers for early diagnosis or predicting prognosis.

ESCRT-I Component VPS23A Is Targeted by E3 Ubiquitin Ligase XBAT35 for Proteasome-Mediated Degradation in Modulating ABA Signaling

A myriad of abiotic stress responses in plants are controlled by abscisic acid(ABA)signaling.ABA receptors can be degraded by both the 26S proteasome pathway and vacuolar degradation pathway after processing via the endosomal sorting complex required for transport(ESCRT)proteins.Despite being essential for ABA signaling,the upstream regulators of ESCRTs remain unknown.Here,we report that the ESCRT-I component VPS23A is an unstable protein that is degraded via the ubiquitin-proteasome system(UPS).The UEV domain of VPS23A physically interacts with the two PSAP motifs of XBAT35,an E3 ubiquitin ligase,and this interaction results in the deposition of K48 polyubiquitin chains on VPS23A,marking it for degradation by 26S proteasomes.We showed that XBAT35 in plants is a positive regulator of ABA responses that acts via the VPS23A/PYL4 complex,specifically by accelerating VPS23A turnover and thereby increasing accumulation of the ABA receptor PYL4.This work deciphers how an ESCRT component is regulated in plants and deepens our understanding of plant stress responses by illustrating a mechanism whereby crosstalk between the UPS and endosome-vacuole-mediated degradation pathways controls ABA signaling.

Immune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch

Protein ubiquitination is an important means of posttranslational modification which plays an essential role in the regulation of various aspects of leukocyte development and function. The specificity of ubiquitin tagging to a protein substrate is determined by E3 ubiquitin ligases via defined E3-substrate interactions. In this review, we will focus on two E3 ligases, VHL and Itch, to discuss the latest progress in understanding their roles in the differentiation and function of CD4+ T helper cell subsets, the stability of regulatory T cells, effector function of CD8+ T cells, as well as the development and maturation of innate lymphoid cells. The biological implications of these E3 ubiquitin ligases will be highlighted in the context of normal and dysregulated immune responses including the control of homeostasis, inflammation, auto-immune responses and anti-tumor immunity. Further elucidation of the ubiquitin system in immune cells will help in the design of new therapeutic interventions for human immunological diseases and cancer.

Ubiquitin ligase DTX3 empowers mutant p53 to promote ovarian cancer development

The deltex family protein DTX3 is believed to possess E3 ubiquitin ligase activity,as it contains a classic RING finger domain.However,its biological role and the underlying mechanism in cancer remain largely elusive.Here,we identified DTX3 as a novel mutant p53-interacting protein in ovarian carcinoma.Mechanistically,DTX3 mediated mutant p53 ubiqui-tination and stabilization by perturbing the MDM2-mutant p53 interaction,consequently leading to activation of diverse.mutant p53 target genes.Importantly,a positive correlation between the expression of DTX3 and mutant p53 target genes was further validated in ovarian carcinomas.Ectopic DTX3 promoted,while depletion of DTX3 suppressed,ovarian cancer cell proliferation and invasion.Remarkably,the pro-tumorigenic effect of DTX3 is dependent on mutant p53,because ablation of mutant p53 significantly impaired DTX3-induced gene expression and ovarian cancer cell growth and propagation.Furthermore,DTX3 elevated the expressi on of muta nt p53 target genes and boosted ovarian tumor growth in vivo.Fin ally,DTX3 was amplified and overexpressed in ovarian carci no mas,which is sign ificantly associated with unfavorable prognosis.Altogether,our findings unveil the oncogenic role of DTX3 in ovarian cancer development by bolstering mutant p53 activity.

The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress glioblastoma progression

Background:Elucidation of the post-transcriptional modification has led to novel strategies to treat intractable tumors,especially glioblastoma(GBM).The ubiquitin-proteasome system(UPS)mediates a reversible,stringent and stepwise post-translational modification which is closely associated with malignant processes of GBM.To this end,developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease.This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM.Based on the molecular identification,functional characterization,and mechanism investigation,we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM.Methods:We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase.Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT,UBA and WWE domain-containing E3 ubiquitin ligase 1(HUWE1)in GBM.dCas9 synergistic activation mediator system and recombinant adeno-associated virus(rAAV)were used to endogenously overexpress full-length HUWE1 in vitro and in glioma orthotopic xenografts.Results:Low expression of HUWE1 was closely associated with worse prognosis of GBM patients.The ubiquitination and subsequent degradation of N-Myc mediated by HUWE1,leading to the inactivation of downstream Delta-like 1(DLL1)-NOTCH1 signaling pathways,inhibited the proliferation,invasion,and migration of GBM cells in vitro and in vivo.A rAAV dual-vector system for packaging and delivery of dCas9-VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts.Conclusions:The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress GBM progression.Antitumor activity of rAAV dual-vector delivering dCas9-HUWE1 system uncovers a promising therapeutic strategy for GBM.

A novel missense mutation of the ubiquitin protein ligase E3A gene in a patient with Angelman syndrome

Background Angelman syndrome （AS） is a neurogenetic disorder caused by an expression defect of the maternally inherited copy of ubiquitin protein ligase E3A （UBE3A） gene from chromosome 15. Although the most common genetic defects include maternal deletions of chromosome 15q11-13, paternal uniparental disomy and imprinting defect, mutations in the UBE3A gene have been identified in approximately 10% of AS patients. Methods A Chinese girl of 28 months presented clinical manifestation of AS. Genetic diagnosis and molecular genetic defects were studied by methylation-specific PCR （MS-PCR） and linkage analysis by short tandem repeat （STR）. We further performed sequence analysis of all the coding exons and flanking sequences of the UBE3A gene. The novel mutation screening was also performed in 100 unrelated healthy individuals to exclude the possibility of identifying a polymorphism variation. Results The MS-PCR analysis of the patient showed biparental inheritance of chromosome 15 with a normal methylation pattern in the 15q11-q13 region. And STR analysis revealed that the patient also inherited biparental alleles for six microsatellites. A novel mutation, cDNA1199 C〉A （p.P400H）, in exon 9 of the maternal UBE3A gene, was identified in the patient. Meanwhile, the mutation was observed in the patient＇s mother who had a normal phenotype. Conclusions It is necessary to perform the UBE3A gene mutation analysis in non-deletion/non-UPD/non-ID patients with AS. The clinical picture of the patient is concordant with that observed in previously reported AS patients with UBE3A mutation.

Drosophila ubiquitin E3 ligase dSmurf is required for synapse remodeling and axon pruning by glia

Animal behaviors and higher-order functions rely on complex neural circuits built by synaptic connections （synapses） to deliver messages among different brain cells. As the major mediator in the nervous system, neurons communicate via synapses, which undergo constant structural remodeling with strict regulation.

The emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance

Epithelial cancer of the ovary exhibits the highest mortality rate of all gynecological malignancies in women today,since the disease is often diagnosed in advanced stages.While the treatment of cancer with specific chemical agents or drugs is the favored treatment regimen,chemotherapy resistance greatly impedes successful ovarian cancer chemotherapy.Thus,chemoresistance becomes one of the most critical clinical issues confronted when treating patients with ovarian cancer.Convincing evidence hints that dysregulation of E3 ubiquitin ligases is a key factor in the development and maintenance of ovarian cancer chemoresistance.This review outlines recent advancement in our understanding of the emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance.We also highlight currently available inhibitors targeting E3 ligase activities and discuss their potential for clinical applications in treating chemoresistant ovarian cancer patients.