Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: July 15, 2022

Increasing evidence has demonstrated that circular RNAs (circRNAs) are implicated in cancer progression. However, the aberrant expression and biological functions of circRNAs clear cell renal carcinoma (cRCC) remain largely elusive.Differentially expressed cRCC were filtered via bioinformatics analysis. Aberrant circPOLR2A was validated tissues lines qRT-PCR. Sanger sequencing used to identify backsplicing site circPOLR2A. In vitro vivo functional experiments performed evaluate role malignancy. RNA pull-down, mass spectrometry, RIP, FISH immunofluorescence assays validate circPOLR2A-interacting proteins. Ubiquitination modification interaction between proteins detected Co-IP western blotting. The m6A by meRIP assay.Bioinformatics analysis revealed highly metastatic tissues. CircPOLR2A associated with tumor size TNM stage patients. accelerated proliferation, migration, invasion angiogenesis, while inhibiting apoptosis. Further mechanistic research suggested could interact UBE3C PEBP1 proteins, act as a specific ubiquitin E3 ligase for protein. UBE3C/circPOLR2A/PEBP1 protein-RNA ternary complex enhanced UBE3C-mediated ubiquitination degradation protein which inactivate ERK signaling pathway. Rescue downstream target Furthermore, confirmed, reader YTHDF2 regulate expression.Our study modulated protein, further activated pathway during progression metastasis. reader, YTHDF2, regulated cRCC. Hence, be potential diagnosis treatment

Language: Английский

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E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(5), P. 3173 - 3194

Published: Feb. 23, 2023

Ubiquitination is a key post-translational modification of proteins, affecting the regulation multiple cellular processes. Cells are equipped with over 600 ubiquitin orchestrators, called E3 ligases, responsible for directing covalent attachment to substrate proteins. Due their regulatory role in cells, significant efforts have been made discover ligands ligases. The recent emergence proteolysis targeting chimera (PROTAC) and molecular glue degrader (MGD) modalities has further increased interest ligases as drug targets. This perspective focuses on how fragment based lead discovery (FBLD) methods used new this important target class. In some cases these led clinical candidates; others, they provided tools deepening our understanding ligase biology. Recently, FBLD-derived inspired design PROTACs that able artificially modulate protein levels cells.

Language: Английский

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Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

Cells, Journal Year: 2023, Volume and Issue: 13(1), P. 29 - 29

Published: Dec. 22, 2023

Ubiquitination is a reversible post-translational modification based on the chemical addition of ubiquitin to proteins with regulatory effects various signaling pathways. can alter molecular functions tagged substrates respect protein turnover, biological activity, subcellular localization or protein–protein interaction. As result, wide variety cellular processes are under ubiquitination-mediated control, contributing maintenance homeostasis. It follows that dysregulation ubiquitination reactions plays relevant role in pathogenic states human diseases such as neurodegenerative diseases, immune-related pathologies and cancer. In recent decades, enzymes ubiquitin–proteasome system (UPS), including E3 ligases deubiquitinases (DUBs), have attracted attention novel druggable targets for development new anticancer therapeutic approaches. This perspective article summarizes peculiarities shared by involved reaction which, when deregulated, lead tumorigenesis. Accordingly, an overview main pharmacological interventions targeting UPS clinical use still trials provided, also highlighting limitations efficacy these Therefore, attempts circumvent drug resistance side well UPS-related emerging technologies therapeutics discussed.

Language: Английский

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Role of protein degradation systems in colorectal cancer

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 14, 2024

Abstract Protein degradation is essential for maintaining protein homeostasis. The ubiquitin‒proteasome system (UPS) and autophagy–lysosome are the two primary pathways responsible directly related to cell survival. In malignant tumors, UPS plays a critical role in managing excessive load caused by cancer cells hyperproliferation. this review, we provide comprehensive overview of dual roles played autolysosome colorectal (CRC), elucidating their impact on initiation progression disease while also highlighting compensatory relationship. Simultaneously targeting both offers new promise enhancing treatment efficacy against CRC. Additionally, apoptosis closely linked ubiquitination autophagy, caspases degrade proteins. A thorough comprehension interplay between various highly important clarifying mechanism underlying onset

Language: Английский

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A de novo ARIH2 gene mutation was detected in a patient with autism spectrum disorders and intellectual disability

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 9, 2024

Abstract E3 ubiquitin protein ligase encoded by ARIH2 gene catalyses the ubiquitination of target proteins and plays a crucial role in posttranslational modifications across various cellular processes. As prior documented, mutations genes involved process are often associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). In current study, de novo heterozygous mutation was identified splicing intronic region adjacent to last exon using whole exome sequencing (WES). We hypothesize that this mutation, found an ASD/ID patient, disrupts Ariadne domain which is autoinhibition enzyme. Predictive analyses elucidated implications novel confirmed its autosomal dominant inheritance model. Nevertheless, we cannot exclude possibility other genetic factors, undetectable WES, such as non-coding regions polygenic risk inter-allelic complementation, may contribute patient's phenotype. This work aims suggest potential relationship between detected both ASD ID, even though functional studies combined new approaches will be necessary validate hypothesis.

Language: Английский

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Circular RNA-mediated miRNA sponge & RNA binding protein in biological modulation of breast cancer

Non-coding RNA Research, Journal Year: 2024, Volume and Issue: 9(1), P. 262 - 276

Published: Jan. 3, 2024

Circular RNAs (circRNAs) and small non-coding of the head-to-junction circle in construct play critical roles gene regulation are significantly associated with breast cancer (BC). Numerous circRNAs potential biomarkers that may be used for diagnosis prognosis. Widespread expression is regarded as a feature highly diverged eukaryotes. Recent studies show have two main biological modulation models: sponging RNA-binding. This review explained biogenesis assessed emerging findings on their sponge function role RNA-binding proteins (RBPs) to better understand how interaction alters cellular BC. We focused sponges affect phenotype progression described exercise translation functions ribosomes. Furthermore, we reviewed recent RBPs, post-protein modifications influencing BC provided perspective future research directions treating

Language: Английский

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Structure and dynamics of a pentameric KCTD5/CUL3/Gβγ E3 ubiquitin ligase complex

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(17)

Published: April 16, 2024

Heterotrimeric G proteins can be regulated by posttranslational modifications, including ubiquitylation. KCTD5, a pentameric substrate receptor protein consisting of an N-terminal BTB domain and C-terminal domain, engages CUL3 to form the central scaffold cullin-RING E3 ligase complex (CRL3 KCTD5 ) that ubiquitylates Gβγ reduces levels in cells. The cryo-EM structure 5:5:5 KCTD5/CUL3 NTD /Gβ 1 γ 2 assembly reveals highly dynamic with rotations over 60° between /CUL3 CTD /Gβγ moieties structure. CRL3 ARIH1 ubiquitylate E3-E3 superassembly, extension include full-length RBX1 ARIH1~ubiquitin conjugate some conformational states position thioester bond within 10 Å lysine-23 Gβ likely represent priming complexes. Most previously described CRL/substrate structures have consisted monovalent complexes involved flexible peptide substrates. shows oligomerization generate polyvalent internal dynamics structured target for ubiquitylation complex.

Language: Английский

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PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 4, 2024

Immunotherapy has been developed, which harnesses and enhances the innate powers of immune system to fight disease, particularly cancer. PD-1 (programmed death-1) PD-L1 death ligand-1) are key components in regulation system, context cancer immunotherapy. regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation glycosylation. PROTACs (Proteolysis Targeting Chimeras) a type new drug design technology. They specifically engineered molecules that target specific proteins within cell for degradation. have designed demonstrated their inhibitory activity against PD-1/PD-L1 pathway, showed ability degrade proteins. In this review, we describe how improve efficacy could be novel strategy combine with radiotherapy, chemotherapy immunotherapy patients.

Language: Английский

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Involvement of E3 ubiquitin ligase NEDD4-mediated YY1 ubiquitination in alleviating idiopathic pulmonary fibrosis

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 269, P. 131976 - 131976

Published: April 30, 2024

Language: Английский

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A pair of E3 ubiquitin ligases control immunity and flowering by targeting different ELF3 proteins in rice

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(20), P. 2731 - 2744.e4

Published: July 17, 2024

Language: Английский

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