Bidirectional interplay between SUMOylation and the tumor suppressor p14ARF
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ABSTRACT:
PROVIDER: PRJNA1166304 | ENA |
REPOSITORIES: ENA
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Project description:Tumor suppressor p14ARF is a lysine-less protein that suppresses tumorigenesis through different mechanisms, including enhancing the SUMOylation of its interactors. Although p14ARF is known to interact with the SUMO conjugating enzyme UBC9, the link between ARF and SUMOylation is poorly understood and the potential impact of SUMOylation on p14ARF is unknown. Herein, we show that p14ARF is modified by SUMO2 in vitro, both in transfected cells and under endogenous conditions. SUMO conjugates to the N-terminal part of the tumor suppressor protein increasing its stability. Degradation of p14ARF protein is induced by UBC9 downmodulation or the inhibition of SUMOylation, and is rescued by the NEDDylation inhibitor MLN4924. Treatment with MLN4924 also promotes p14ARF SUMOylation and the transcriptional transactivation of the SUMOylation machinery components SUMO1, SUMO2 and UBC9. This causes a global increase in SUMOylation that contributesto the upregulation of p14ARF levels. Importantly, p14ARF is required for the global increase in SUMOylation induced by MLN4924, and it plays an important role in the cytotoxic effect of the NEDDylation inhibitor on prostate cancer cells. Our results provide evidence that lysine-independent SUMOylation of p14ARF is a new post-translational mechanism regulating p14ARF stability and establishes a new link between inhibition of NEDDylation and SUMOylation.
2025-07-30 | GSE278308 | GEO
Project description:35 Melanoma cell lines hybridized to Affymetrix Hu133_Plus 2 microarrays were analysed for genes differentially expressed between cell lines carrying wild-type p14ARF and those with mutant 14ARF. All of these cell lines contained wild-type p53 (so that the effects of p14ARF mutations could be analysed without contamination from p53). Keywords: Affymetrix Hu133_Plus microarrays
2007-03-31 | GSE7152 | GEO
Project description:35 Melanoma cell lines hybridized to Affymetrix Hu133_Plus 2 microarrays were analysed for genes differentially expressed between cell lines carrying wild-type p14ARF and those with mutant 14ARF. All of these cell lines contained wild-type p53 (so that the effects of p14ARF mutations could be analysed without contamination from p53). Experiment Overall Design: The aim of this study was to identify downstream effectors of p14ARF in melanoma. Relevant paper: Packer et al. (2007) Int J Cancer.
2008-06-15 | E-GEOD-7152 | biostudies-arrayexpress
Project description:Foxp3-expressing regulatory T (Treg) cells are essential regulators in the immune system; molecular mechanisms underlying Treg cell expansion and function are still not well understood. SUMOylation is an important post-translational modification characterized by covalent attachment of SUMO moieties to lysine within proteins. UBC9 is the only E2 conjugation enzyme involved in this process and loss of UBC9 completely impairs the SUMOylation pathway. Here we report that selective deletion of Ubc9 within the Treg cell lineage resulted in fatal early-onset autoimmunity as the Foxp3 mutant mice. Ubc9-deficient Treg cells exhibited severe defects in TCR-driven homeostatic proliferation, accompanied by impaired activation and compromised suppressor function. Importantly, TCR-enhanced SUMOylation of IRF4, a critical regulator of Treg cell function downstream of TCR signals, regulates its stability in Treg cells. Our data thus have demonstrated an essential role of SUMOylation in the expansion and function of Treg cells. RNA-seq library was generated using mRNA of CD4+ YFP+ Treg cells sorted from lymph nodes and spleen of Foxp3cre/wtUbc9fl/wt or Foxp3cre/wtUbc9fl/fl mice, each sample contained pooled Treg cells from 5~10 mice.
2016-05-31 | E-GEOD-82031 | biostudies-arrayexpress
Project description:To gain insight into the impact of THO complex sumoylation on gene expression in yeast S. cerevisiae, total RNAs were extracted from wt and hpr1-KR cells and transcriptome profiles were analyzed by Agilent microarrays. The hpr1 K-R mutant is a version of the hpr1 THO subunit in which lysines 60-65 were simultaneously mutated, which abrogated the sumoylation of the protein.
2014-01-25 | E-MTAB-2138 | biostudies-arrayexpress
Project description:Foxp3-expressing regulatory T (Treg) cells are essential regulators in the immune system; molecular mechanisms underlying Treg cell expansion and function are still not well understood. SUMOylation is an important post-translational modification characterized by covalent attachment of SUMO moieties to lysine within proteins. UBC9 is the only E2 conjugation enzyme involved in this process and loss of UBC9 completely impairs the SUMOylation pathway. Here we report that selective deletion of Ubc9 within the Treg cell lineage resulted in fatal early-onset autoimmunity as the Foxp3 mutant mice. Ubc9-deficient Treg cells exhibited severe defects in TCR-driven homeostatic proliferation, accompanied by impaired activation and compromised suppressor function. Importantly, TCR-enhanced SUMOylation of IRF4, a critical regulator of Treg cell function downstream of TCR signals, regulates its stability in Treg cells. Our data thus have demonstrated an essential role of SUMOylation in the expansion and function of Treg cells.
2016-05-31 | GSE82031 | GEO
Project description:Gastric cancer (GC) remains a significant health challenge due to its high mortality rate and the limited efficacy of current targeted therapies. A critical barrier in developing more effective treatments is the lack of understanding of specific mechanisms driving GC progression. This study investigates the role of Transient Receptor Potential Vanilloid 1 (TRPV1), a non-selective cation channel known for its high Ca2+ permeability and tumor-suppressive properties in gastrointestinal cancers. Specifically, we explore the impact of SUMOylation—a dynamic and reversible post-translational modification—on TRPV1's function in GC. We demonstrate that SUMOylation of TRPV1 inhibits cell proliferation and migration in MGC-803 and AGS gastric cancer cells. By mutating amino acids near TRPV1's existing SUMO motif (slKpE), we created a bidirectional SUMO motif (EψKψE) that enhances TRPV1 SUMOylation, resulting in further suppression of GC cell proliferation and migration. In vivo studies support these findings, showing that TRPV1 SUMOylation prevents spontaneous tumorigenesis in a mouse gastric cancer model. Further investigation reveals that TRPV1 SUMOylation increases the protein's membrane expression by inhibiting its interaction with the adaptor-related protein complex 2 mu 1 subunit (AP2M1). This elevated membrane expression leads to increased intracellular Ca2+ influx, activating the AMP-activated protein kinase (AMPK) pathway, which in turn inhibits the proliferation and migration of GC cells. In conclusion, our study elucidates a novel mechanism wherein TRPV1 SUMOylation promotes its membrane expression and activates the TRPV1-Ca2+-AMPK signaling pathway, thereby inhibiting GC cell proliferation and migration. These findings enhance our understanding of the molecular dynamics in gastric cancer and could provide a new theoretical basis for clinical treatment strategies.
2024-10-15 | GSE262378 | GEO
Project description:Unrestricted SUMOylation drives lymphomagenesis
2021-10-11 | GSE141913 | GEO
Project description:The 9p21 locus encodes tumor suppressors p16INK4A and p14ARF (both encoded by CDKN2A), p15INK4B (CDKN2B), and a long non-coding RNA, ANRIL (CDKN2B-AS1). The ~1 megabase locus is notable for a high density of single nucleotide polymorphisms (SNPs) associated with aging-related diseases and traits. Despite clear importance, our understanding of the the cell-type specific expression dynamics and cis-regulatory mechanisms of the 9p21 transcripts has been constrained by the complexity of the transcript structures, low expression, and severe alterations to the locus in cancer cell lines. Here, we innovated custom computational and molecular tools to overcome these technical challenges and fill critical knowledge gaps in our understanding of 9p21 locus architecture and regulation of the 9p21 transcripts. Across tissues, we found that p15INK4b is the predominant transcript. We deconvolved the expression of the CDKN2A transcripts, p16INK4A and p14ARF, revealing stark differences in the expression of these overlapping but functionally distinct transcripts across tissues and cell types. Comparative analysis in a model of fibroblast senescence revealed a striking switch from preferential p14ARF expression in cycling cells, to p16INK4A and p15INK4b as cells age and senescence. Perturbation of putative cis regulatory elements nominated a network of promoters and enhancers that regulate p16INK4A, p14ARF, and p15INK4b and ANRIL. The identified elements are accessible in vivo, and can be used to guide studies into variant interpretation. Our systematic characterization of 9p21 transcript isoforms, promoters, and distal elements across cell states, in vivo tissues and senescence offers new mechanistic insights and a framework for future studies of this vital but poorly understood locus.
2026-06-29 | GSE309495 | GEO
Project description:The 9p21 locus encodes tumor suppressors p16INK4A and p14ARF (both encoded by CDKN2A), p15INK4B (CDKN2B), and a long non-coding RNA, ANRIL (CDKN2B-AS1). The ~1 megabase locus is notable for a high density of single nucleotide polymorphisms (SNPs) associated with aging-related diseases and traits. Despite clear importance, our understanding of the the cell-type specific expression dynamics and cis-regulatory mechanisms of the 9p21 transcripts has been constrained by the complexity of the transcript structures, low expression, and severe alterations to the locus in cancer cell lines. Here, we innovated custom computational and molecular tools to overcome these technical challenges and fill critical knowledge gaps in our understanding of 9p21 locus architecture and regulation of the 9p21 transcripts. Across tissues, we found that p15INK4b is the predominant transcript. We deconvolved the expression of the CDKN2A transcripts, p16INK4A and p14ARF, revealing stark differences in the expression of these overlapping but functionally distinct transcripts across tissues and cell types. Comparative analysis in a model of fibroblast senescence revealed a striking switch from preferential p14ARF expression in cycling cells, to p16INK4A and p15INK4b as cells age and senescence. Perturbation of putative cis regulatory elements nominated a network of promoters and enhancers that regulate p16INK4A, p14ARF, and p15INK4b and ANRIL. The identified elements are accessible in vivo, and can be used to guide studies into variant interpretation. Our systematic characterization of 9p21 transcript isoforms, promoters, and distal elements across cell states, in vivo tissues and senescence offers new mechanistic insights and a framework for future studies of this vital but poorly understood locus.
2026-06-29 | GSE309493 | GEO