scholarly journals E3 ubiquitin ligase HECTD2 mediates melanoma progression and immune evasion

Oncogene ◽  
2021 ◽  
Author(s):  
Eleonora Ottina ◽  
Veera Panova ◽  
Laura Doglio ◽  
Anastasiya Kazachenka ◽  
Georgina Cornish ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cancer Cell ◽  
Ubiquitin Ligase ◽  
Immune Evasion ◽  
Tumour Progression ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Tumour Immunity ◽  
Murine Melanoma

AbstractThe ubiquitin-proteasome system maintains protein homoeostasis, underpins the cell cycle, and is dysregulated in cancer. However, the role of individual E3 ubiquitin ligases, which mediate the final step in ubiquitin-mediated proteolysis, remains incompletely understood. Identified through screening for cancer-specific endogenous retroviral transcripts, we show that the little-studied E3 ubiquitin ligase HECTD2 exerts dominant control of tumour progression in melanoma. HECTD2 cell autonomously drives the proliferation of human and murine melanoma cells by accelerating the cell cycle. HECTD2 additionally regulates cancer cell production of immune mediators, initiating multiple immune suppressive pathways, which include the cyclooxygenase 2 (COX2) pathway. Accordingly, higher HECTD2 expression is associated with weaker anti-tumour immunity and unfavourable outcome of PD-1 blockade in human melanoma and counteracts immunity against a model tumour antigen in murine melanoma. This central, multifaceted role of HECTD2 in cancer cell-autonomous proliferation and in immune evasion may provide a single target for a multipronged therapy of melanoma.

scholarly journals p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex

2017 ◽  
Vol 37 (8) ◽  
Author(s):  
Shasha Tao ◽  
Pengfei Liu ◽  
Gang Luo ◽  
Montserrat Rojo de la Vega ◽  
Heping Chen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Complexes ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Client Proteins

ABSTRACT Activation of the stress-responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targeted to the proteasome for degradation (the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation was previously unknown. p97 is a ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system (UPS). In this study, we show that p97 negatively regulates NRF2 through the canonical pathway by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric cofactor UFD1/NPL4 and the UBA-UBX-containing protein UBXN7, for efficient proteasomal degradation. Given the role of NRF2 in chemoresistance and the surging interest in p97 inhibitors to treat cancers, our results indicate that dual p97/NRF2 inhibitors may offer a more potent and long-term avenue of p97-targeted treatment.

scholarly journals MEKK5 Interacts with and Negatively Regulates the E3 Ubiquitin Ligase NEDD4 for Mediating Lung Cancer Cell Migration

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1153
Author(s):  
Aiqin Sun ◽  
Jun Zhu ◽  
Song Xia ◽  
Yanling Li ◽  
Tiantian Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Cancer Cell ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Cancer Cell Migration ◽  
Lung Cancer Cell ◽  
Cancer Migration ◽  
Ubiquitination Assay

Our previous studies have shown that the HECT E3 ubiquitin ligase NEDD4 and kinase MEKK5 both play an essential role in lung cancer migration. A report predicts that MEKK5 may be ubiquitinated by NEDD4; however, interaction of MEKK5 with NEDD4 and ubiquitination of MEKK5 by NEDD4 have not been characterized. In this report, we show that NEDD4 interacts with MEKK5 through a conserved WW3 domain by the co-immunoprecipitation and the GST-pulldown assays. The ubiquitination assay indicates that MEKK5 is not a ubiquitination substrate of NEDD4, but negatively regulates NEDD4-mediated ubiquitination. Furthermore, overexpression of MEKK5 significantly reduced the NEDD4-promoted lung cancer cell migration. Taken together, our studies have defined an inhibitory role of MEKK5 in regulation of NEDD4-mediated ubiquitination.

scholarly journals Defining the Interactions and Role of DCAF1/VPRBP in the DDB1-Cullin4A E3 Ubiquitin Ligase Complex Engaged by HIV-1 Vpr to Induce a G2 Cell Cycle Arrest

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e89195 ◽  
Author(s):  
Francine C. A. Gérard ◽  
Ruifeng Yang ◽  
Bizhan Romani ◽  
Alexis Poisson ◽  
Jean-Philippe Belzile ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Cycle Arrest ◽  
Ubiquitin Ligase Complex ◽  
G2 Cell Cycle Arrest ◽  
Hiv 1

scholarly journals Role of the E3 ubiquitin ligase RNF157 as a novel downstream effector linking PI3K and MAPK signaling pathways to the cell cycle

2017 ◽  
Vol 292 (35) ◽  
pp. 14311-14324 ◽  
Author(s):  
Taner Dogan ◽  
Florian Gnad ◽  
Jocelyn Chan ◽  
Lilian Phu ◽  
Amy Young ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signaling Pathways ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Mapk Signaling ◽  
Downstream Effector ◽  
Mapk Signaling Pathways

scholarly journals The potential oncogenic and MLN4924-resistant effects of CSN5 on cervical cancer cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Huilin Zhang ◽  
Ping He ◽  
Qing Zhou ◽  
Yan Lu ◽  
Bingjian Lu
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cervical Cancer Cell ◽  
Cervical Cancers ◽  
Cervical Cancer Cells

Abstract Background CSN5, a member of Cop9 signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. However, the role of CSN5 has not been investigated in cervical cancer yet. Methods Data from TCGA cohorts and GEO dataset was analyzed to examine the expression profile of CSN5 and clinical relevance in cervical cancers. The role of CSN5 on cervical cancer cell proliferation was investigated in cervical cancer cell lines, Siha and Hela, through CSN5 knockdown via CRISPR–CAS9. Western blot was used to detect the effect of CSN5 knockdown and overexpression. The biological behaviors were analyzed by CCK8, clone formation assay, 3-D spheroid generation assay and cell cycle assay. Besides, the role CSN5 knockdown in vivo was evaluated by xenograft tumor model. MLN4924 was given in Siha and Hela with CSN5 overexpression. Results We found that downregulation of CSN5 in Siha and Hela cells inhibited cell proliferation in vitro and in vivo, and the inhibitory effects were largely rescued by CSN5 overexpression. Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis. Importantly, CSN5 overexpression confers resistance to the anti-cancer effects of MLN4924 (pevonedistat) in cervical cancer cells. Conclusions Our findings demonstrated that CSN5 functions as an oncogene in cervical cancers and may serve as a potential indicator for predicting the effects of MLN4924 treatment in the future.

The Potential Oncogenic and MLN4924-Resistant Effects of CSN5 on Cervical Cancer Cells

2021 ◽  
Author(s):  
Huilin Zhang ◽  
Ping He ◽  
Qing Zhou ◽  
Yan Lu ◽  
Bingjian Lu
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cervical Cancer Cell ◽  
Cervical Cancers ◽  
Cervical Cancer Cells

Abstract BackgroundsCSN5, a member of Cop9 signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. However, the role of CSN5 has not been investigated in cervical cancer yet.MethodsData from TCGA cohorts and GEO dataset was analyzed to examine the expression profile of CSN5 in cervical cancers. The role of CSN5 on cervical cancer cell proliferation was investigated in cervical cancer cell lines, Siha and Hela, through CSN5 knockdown via CRISPR-CAS9. Western blot was used to detect the effect of CSN5 knockdown and overexpression. CCK8, clone formation assay and cell cycle assay were also employed. Besides, the role CSN5 knockdown in vivo was evaluated by xenograft tumor model. Moreover, MLN4924 was applied in Siha and Hela with CSN5 overexpression.ResultsWe found that downregulation of CSN5 in Siha and Hela cells inhibited cell proliferation in vitro and in vivo, and the inhibitory effects were largely rescued by CSN5 overexpression. Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis. Importantly, CSN5 overexpression confers resistance to the anti-cancer effects of MLN4924 (pevonedistat) in cervical cancer cells.ConclusionsOur findings demonstrated that CSN5 functions as an oncogene in cervical cancers and may serve as a potential indicator for predicting the effects of MLN4924 treatment in the future.

Activation mechanisms of the E3 ubiquitin ligase parkin

2017 ◽  
Vol 474 (18) ◽  
pp. 3075-3086 ◽  
Author(s):  
Nikhil Panicker ◽  
Valina L. Dawson ◽  
Ted M. Dawson
Keyword(s):  
Parkinson’S Disease ◽  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Recent Literature ◽  
E3 Ubiquitin Ligase ◽  
Mitochondrial Damage ◽  
Cytosolic Protein ◽  
Mitochondrial Functions ◽  
Activation Mechanisms

Monogenetic, familial forms of Parkinson's disease (PD) only account for 5–10% of the total number of PD cases, but analysis of the genes involved therein is invaluable to understanding PD-associated neurodegenerative signaling. One such gene, parkin, encodes a 465 amino acid E3 ubiquitin ligase. Of late, there has been considerable interest in the role of parkin signaling in PD and in identifying its putative substrates, as well as the elucidation of the mechanisms through which parkin itself is activated. Its dysfunction underlies both inherited and idiopathic PD-associated neurodegeneration. Here, we review recent literature that provides a model of activation of parkin in the setting of mitochondrial damage that involves PINK1 (PTEN-induced kinase-1) and phosphoubiquitin. We note that neuronal parkin is primarily a cytosolic protein (with various non-mitochondrial functions), and discuss potential cytosolic parkin activation mechanisms.

scholarly journals Hect E3 ubiquitin ligase Tom1 controls Dia2 degradation during the cell cycle

2012 ◽  
Vol 23 (21) ◽  
pp. 4203-4211 ◽  
Author(s):  
Dong-Hwan Kim ◽  
Deanna M. Koepp
Keyword(s):  
Cell Cycle ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
S Phase ◽  
Temperature Sensitive ◽  
Dependent Manner ◽  
Charged Residues ◽  
Phase Progression ◽  
Positively Charged

The ubiquitin proteasome system plays a pivotal role in controlling the cell cycle. The budding yeast F-box protein Dia2 is required for genomic stability and is targeted for ubiquitin-dependent degradation in a cell cycle–dependent manner, but the identity of the ubiquitination pathway is unknown. We demonstrate that the Hect domain E3 ubiquitin ligase Tom1 is required for Dia2 protein degradation. Deletion of DIA2 partially suppresses the temperature-sensitive phenotype of tom1 mutants. Tom1 is required for Dia2 ubiquitination and degradation during G1 and G2/M phases of the cell cycle, whereas the Dia2 protein is stabilized during S phase. We find that Tom1 binding to Dia2 is enhanced in G1 and reduced in S phase, suggesting a mechanism for this proteolytic switch. Tom1 recognizes specific, positively charged residues in a Dia2 degradation/NLS domain. Loss of these residues blocks Tom1-mediated turnover of Dia2 and causes a delay in G1–to–S phase progression. Deletion of DIA2 rescues a delay in the G1–to–S phase transition in the tom1Δ mutant. Together our results suggest that Tom1 targets Dia2 for degradation during the cell cycle by recognizing positively charged residues in the Dia2 degradation/NLS domain and that Dia2 protein degradation contributes to G1–to–S phase progression.

scholarly journals Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling

2021 ◽  
Vol 118 (25) ◽  
pp. e2104944118
Author(s):  
Sara E. Konopelski Snavely ◽  
Michael W. Susman ◽  
Ryan C. Kunz ◽  
Jia Tan ◽  
Srisathya Srinivasan ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Large Scale ◽  
Glycogen Synthase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Dependent Manner ◽  
Casein Kinase 1 ◽  
Downstream Signaling ◽  
Proteomic Screen ◽  
Responsive Element

Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate development [R. T. Moon et al., Development 119, 97–111 (1993); I. Oishi et al., Genes Cells 8, 645–654 (2003)], but its downstream signaling events remain poorly understood. Through a large-scale proteomic screen in mouse embryonic fibroblasts, we identified the E3 ubiquitin ligase Pdzrn3 as a regulatory target of the Wnt5a-Ror pathway. Upon pathway activation, Pdzrn3 is degraded in a β-catenin–independent, ubiquitin-proteasome system–dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, Casein kinase 1, and Glycogen synthase kinase 3 that regulates Pdzrn3 stability. Epistatically, Pdzrn3 is regulated independently of Kif26b, another Wnt5a-Ror effector. Wnt5a-dependent degradation of Pdzrn3 requires phosphorylation of three conserved amino acids within its C-terminal LNX3H domain [M. Flynn, O. Saha, P. Young, BMC Evol. Biol. 11, 235 (2011)], which acts as a bona fide Wnt5a-responsive element. Importantly, this phospho-dependent degradation is essential for Wnt5a-Ror modulation of cell migration. Collectively, this work establishes a Wnt5a-Ror cell morphogenetic cascade involving Pdzrn3 phosphorylation and degradation.

Sign in / Sign up

Export Citation Format

Share Document