Ontology highlight
ABSTRACT:
PROVIDER: PRJNA344797 | ENA |
REPOSITORIES: ENA
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Project description:The E3 ligase MDM2 promotes tumor growth and progression by inducing ubiquitin-mediated degradation of P53 and other tumor suppressing proteins. Here, we identified an MDM2-interacting lncRNA NRON, which promotes tumor formation by suppressing both P53-dependent and independent pathways. NRON binds to MDM2 and MDMX (MDM4) via two different stem-loops respectively and induces their heterogenous dimerization, thereby enhancing the E3 ligase activity of MDM2 towards its tumor suppressing substrates, including P53, RBI and NFATI, etc.
2023-06-19 | GSE226511 | GEO
Project description:Histone deacetylases (HDACs) are promising targets for cancer therapy, while their individual actions remain incompletely understood. Here, we identify a role for HDAC2 in regulation of
MDM2 acetylation at previously uncharacterized lysines. Upon inactivation of HDAC2, this acetylation creates a structural signal in the lysine-rich domain of MDM2 to prevent the recognition and degradation of its downstream substrate, MCL-1 Ubiquitin Ligase E3 (MULE). This mechanism further reveals a therapeutic connection between the MULE ubiquitin ligase function and tumor suppression. Specifically, we show that HDAC inhibitor treatment promotes the accumulation of MULE, which diminishes the t(X;18) translocation-associated synovial sarcomagenesis by directly targeting the fusion product SS18-SSX for degradation. These results
uncover a new HDAC2-dependent pathway that integrates reversible acetylation signaling to the anticancer ubiquitin response.
2020-03-22 | PXD012540 | JPOST Repository
Project description:Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We demonstrate that EZH2 interacts with both MYC family oncoproteins, C-MYC and N-MYC, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFbw7 ubiquitin ligase to bind MYC, EZH2 counteracted Fbw7-mediated MYC polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induced robust MYC degradation and inhibited tumor cell growth in MYC-driven neuroblastoma and small-cell lung cancer. These findings unveil the MYC family proteins as critical EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC-selective cancer therapeutics, pointing out that MYC-driven cancers may develop inherent resistance to canonical EZH2 enzymatic inhibitors currently in clinical development.
2021-08-31 | GSE181782 | GEO
Project description:Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We demonstrate that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracted FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induced robust MYC(N) degradation and inhibited tumor cell growth in MYC(N) driven neuroblastoma and small cell lung cancer. These findings unveil the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.
2022-02-17 | PXD029652 | Pride
Project description:PROteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS032, a CDK9 inhibitor. The lead conjugate 955 can potently degrade CDK9 in a ubiquitin-proteasome-dependent manner and is much more potent than SNS-032 against various tumor cells in vitro. Mechanistically, we identified KEAP1 as the E3 ligase recruited by 955 to degrade CDK9 through a TurboID-based proteomics study, which was further confirmed by KEAP1 knockout and the nanoBRET ternary complex formation assay. In addition, PL-Ceritinib conjugate can degrade EML4-ALK fusion oncoprotein, suggesting that PL may have a broader application as a covalent E3 ligase ligand in targeted protein degradation.
2022-06-26 | GSE206612 | GEO
Project description:Muscle atrophy F-box (MAFbx) is an E3 ubiquitin ligase which plays a critical role in mediating skeletal muscle atrophy. We investigated the effect of MAFbx KO in cardiac hypertrophy in response to pressure overload. A DNA microarray analysis was conducted using total RNA prepared from wild type and MAFbx KO mouse hearts subject to transverse aortic constriction (TAC). Results provide insight into the molecular mechanism to mediate the effect of MAFbx upon pathological hypertrophy. We applied TAC to wild type and MAFbx KO mice, and extracted total RNA one week after the surgery. The gene expression profiles were examined by Affymetrix Mouse Gene ST Array.
2011-05-01 | E-GEOD-24372 | biostudies-arrayexpress
Project description:Brassinosteroids (BRs) regulate plant growth, development and stress responses by activating the core transcription factor BRI1-EMS-SUPPRESSOR1 (BES1). The E3 Ubiquitin ligase(s) that modify BES1 for autophagy-mediated degradation remain to be fully defined. In this study, we identified an F-box family E3 ubiquitin ligase termed BES1-ASSOCIATED F-BOX1 (BAF1). BAF1 interacts with and ubiquitinates BES1. Accordingly, BES1 stability and protein levels were reduced in BAF1 overexpression plants but increased in a baf1 loss-of-function mutant and in BAF1-DF (BAF1 with F-box deleted, dominant-negative form) overexpression lines. Selective autophagy of BES1, but not bulk autophagy, was significantly compromised in the baf1 mutant under sucrose starvation. BES1 degradation mediated by BAF1 could be blocked through autophagy but not proteasome inhibitors, suggesting that BAF1 mediates BES1 degradation largely through autophagy. baf1 and BAF1-DF overexpression plants had increased BR-regulated growth but were sensitive to long-term sucrose starvation, while BAF1 overexpression plants had decreased BR-regulated growth but were highly tolerant of sucrose starvation. Our results not only established BAF1 as a novel E3 ubiquitin ligase that targets BES1 for degradation through selective autophagy pathway, but also revealed a mechanism for plants to reduce growth during sucrose starvation by targeting this central growth regulator.
2022-08-01 | GSE155219 | GEO
Project description:Muscle atrophy F-box (MAFbx) is an E3 ubiquitin ligase which plays a critical role in mediating skeletal muscle atrophy. We investigated the effect of MAFbx KO in cardiac hypertrophy in response to pressure overload. A DNA microarray analysis was conducted using total RNA prepared from wild type and MAFbx KO mouse hearts subject to transverse aortic constriction (TAC). Results provide insight into the molecular mechanism to mediate the effect of MAFbx upon pathological hypertrophy.
2011-05-01 | GSE24372 | GEO
Project description:The tumor suppressor BRCA1 regulates DNA damage responses and multiple other processes. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal RING domain. Here we show that BRCA1 promotes oxidative metabolism via degradation of Oct1, a transcription factor with pro-glycolytic/tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells towards a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype. RNAseq confirms the deregulation of metabolic genes. BRCA1 mediates direct Oct1 ubiquitylation and degradation, and mutation of two ubiquitylated Oct1 lysines insulates the protein against BRCA1-mediated destabilization. Oct1 deletion in MCF-7 breast cancer cells does not perturb growth in standard culture, but inhibits growth in soft agar and xenografts. Oct1 protein levels correlate positively with tumor aggressiveness, and inversely with BRCA1, in primary breast cancer samples. These results identify BRCA1 as an Oct1 ubiquitin ligase that catalyzes Oct1 degradation to promote oxidative metabolism.
2017-11-30 | GSE98831 | GEO
Project description:Analysis of gene expression altered upon knockdown of Siah2 in prosate cancer cells. The objective is to elucidate which signaling pathways or transcription factors are regulated by the E3 ubiquitin ligase Siah2 in human prostate cancer cells.
2013-03-19 | GSE38851 | GEO