P53 Promotes Peroxisomal Fatty Acid β-oxidation to Repress Purine metabolism and Mediate Tumor Suppression
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ABSTRACT:
PROVIDER: PRJNA784283 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17055650_1.fastq.gz | Fastqsanger.gz | |||
| SRR17055650_2.fastq.gz | Fastqsanger.gz | |||
| SRR17055651_1.fastq.gz | Fastqsanger.gz | |||
| SRR17055651_2.fastq.gz | Fastqsanger.gz | |||
| SRR17055652_1.fastq.gz | Fastqsanger.gz |
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Project description:The metabolic pathways through which p53 functions as a potent tumor suppressor are incompletely understood. Here we report that, by associating with the Vitamin D receptor (VDR), p53 induces numerous genes encoding enzymes for peroxisomal fatty acid β-oxidation (FAO). This leads to increased cytosolic acetyl-CoA levels and acetylation of the enzyme 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC), which catalyzes the last two steps in the purine biosynthetic pathway. This acetylation step, mediated by lysine acetyltransferase 2B (KAT2B), occurs at ATIC Lys 266, dramatically inhibits ATIC activity, and inversely correlates with colorectal cancer (CRC) tumor growth in vitro and in vivo, and acetylation of ATIC is downregulated in human CRC samples. p53-deficient CRCs with high levels of ATIC is more susceptible to ATIC inhibition. Collectively, these findings link p53 to peroxisomal FAO, purine biosynthesis, and CRC pathogenesis in a manner that is regulated by the levels of ATIC acetylation.
| S-EPMC9905075 | biostudies-literature
Project description:Several studies suggested that p53 controls multiple metabolic pathways and their contribution to its tumor-suppressive functions. To investigate whether p53 might involve some unexplored metabolic pathways, Trp53fl/fl mice were crossed with Pvillin-Cre mice to generate Pvillin-Cre + Trp53fl/fl (VP) mice, and colorectal tumor model was induced by AOM/DSS. We analyzed the CRC tumor tissues from Trp53fl/fl and VP mice by RNA-seq.
2023-03-02 | GSE189730 | GEO
Project description:Robust tissue regeneration relies on extensive stem cell self-renewal. However, the molecular mechanisms promoting stem cell self-renewal during regeneration remain unclear. Here we investigate the role of peroxisomes, a key metabolic organelle, in regulating hematopoietic stem cells (HSCs). We found that disrupting peroxisome biogenesis by deleting Pex5 does not significantly impact HSC number or hematopoiesis at steady state. Strikingly, Pex5-deficient HSCs self-renew extensively and give rise to robust multilineage reconstitution upon multiple rounds of serial transplantation into recipients. Pex5-deficient HSCs are more resistant to stress and have enhanced capacity to regenerate the hematopoietic system following chemo drug treatment or irradiation. Deletion of Pex5 promotes the expansion of HSCs and hematopoietic progenitors with extensive serial ex vivo plating capacity. Pharmacological inhibition of peroxisomal β-oxidation also promotes extensive plating by HSCs and hematopoietic progenitors. We propose that intervening in peroxisomal β-oxidation can be exploited to promote HSC and progenitor function for regenerative medicine.
2025-09-01 | GSE294155 | GEO
Project description:Distinct retrograde signaling pathways have been identified for several cellular organelles. These pathways are important to maintain the function of these organelles in response to organelle-specific stress. Using Caenorhabditis elegans, we show for the first time that such a retrograde signaling also exists for peroxisomes. Analysis of the C. elegans transcriptome revealed that peroxisomal import stress caused by the knock-down of the peroxisomal matrix protein import receptor prx-5/PEX5 induces the compensatory up-regulation of genes involved in defense response and lipid metabolic processes, especially peroxisomal beta oxidation. We, therefore, propose that the peroxisomal retrograde signaling participates in the maintenance of peroxisomal function in response to peroxisomal import stress.
2020-12-19 | GSE156318 | GEO
Project description:Epigenetic markers such as histone acetylation and DNA methylation determine chromatin organization. In eukaryotic cells, metabolites from organelles or the cytosol affect epigenetic modifications. However, the relationships between metabolites and epigenetic modifications are not well understood in plants. We found that peroxisomal acyl-CoA oxidase 4 (ACX4), an enzyme in the fatty acid β-oxidation pathway, is required for suppressing the silencing of some endogenous loci as well as Pro35S:NPTII in the ProRD29A:LUC/C24 transgenic line. The acx4 mutation reduces nuclear histone acetylation and increases DNA methylation at the NOS terminator of Pro35S:NPTII, and at some endogenous genomic loci, which are also targeted by the demethylation enzyme REPRESSOR OF SILENCING 1 (ROS1). Furthermore, mutations in multifunctional protein 2 (MFP2) and 3-ketoacyl-CoA thiolase-2 (KAT2/PED1/PKT3), two enzymes in the last two steps of the β-oxidation pathway, lead to similar patterns of DNA hypermethylation as in acx4. Thus, metabolites from fatty acid β-oxidation in peroxisomes are closely linked to nuclear epigenetic modifications, which may affect diverse cellular processes in plants.
2018-04-25 | GSE98214 | GEO
Project description:Peroxisomes are central metabolic organelles that have key roles in fatty acid homeostasis, including β-oxidation, and emerging evidence has linked aberrant peroxisome metabolism to cancer development and progression. While targeting mitochondrial β-oxidation in prostate cancer (PCa) has gained significant attention in recent years, the contribution of peroxisomal β-oxidation (perFAO) to PCa tumorigenesis is comparatively unexplored. Herein, we explored the therapeutic efficacy of targeting perFAO in PCa cells and clinical prostate tumours, and subsequently identified peroxisomal 2,4-dienoyl CoA reductase 2 (DECR2), as a key therapeutic target. DECR2 is markedly upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa. Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and enzalutamide-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. Using transcriptomic and lipidomic analyses, we determined that DECR2 influences cell cycle progression and lipid metabolism to enable tumour cell proliferation. We further demonstrated a novel role for perFAO in driving resistance to standard-of-care androgen receptor pathway inhibition, using genetic and pharmacological approaches to alter DECR2/perFAO in treatment-resistant PCa cells. Our findings highlight a need to focus on peroxisomes to suppress tumour cell proliferation and reveal new therapeutic targets for advanced, treatment-resistant PCa.
2023-12-31 | GSE218282 | GEO
Project description:The aim is to study the function of peroxisomal NAD-malate dehydrogenase in fatty acid beta-oxidation, glyoxylate cycle and photorespiration. Both peroxisomal MDH genes (At2g22780 and At5g09660) have been knocked out with T-DNA insertions and a double mutant made. Double mutant seedlings are blocked in beta-oxidation - they are 2,4DB resistant and beta-oxidation genes are repressed. They carry out glyoxylate cycle as normal. Plants grow well in soil and produce seed. Microarray analysis will tell us the extent of changes in gene expression in the mutant. For microarray analysis seeds are stratified at 4 C on agar medium with 1/2 strength M&S salts and 1% sucrose for 2 days, then seedlings grown for 2 days at 20 C in the light (100 umol/m2/s). Triplicate samples will be grown for mutant and wild type (col-0) and RNA isolated from each. Experimenter name = Itsara Pracharoenwattana; Experimenter phone = 0131 650 5316; Experimenter fax = 0131 650 5392; Experimenter department = Institute of Molecular Plant Sciences; Experimenter institute = University of Edinburgh; Experimenter address = Daniel Rutherford Building University of Edinburgh; Experimenter address = The King's Buildings; Experimenter address = Edinburgh; Experimenter zip/postal_code = EH9 3JH; Experimenter country = UK Experiment Overall Design: 6 samples were used in this experiment
2008-06-13 | E-GEOD-5641 | biostudies-arrayexpress
Project description:The aim is to study the function of peroxisomal NAD-malate dehydrogenase in fatty acid beta-oxidation, glyoxylate cycle and photorespiration. Both peroxisomal MDH genes (At2g22780 and At5g09660) have been knocked out with T-DNA insertions and a double mutant made. Double mutant seedlings are blocked in beta-oxidation - they are 2,4DB resistant and beta-oxidation genes are repressed. They carry out glyoxylate cycle as normal. Plants grow well in soil and produce seed. Microarray analysis will tell us the extent of changes in gene expression in the mutant. For microarray analysis seeds are stratified at 4 C on agar medium with 1/2 strength M&S salts and 1% sucrose for 2 days, then seedlings grown for 2 days at 20 C in the light (100 umol/m2/s). Triplicate samples will be grown for mutant and wild type (col-0) and RNA isolated from each. Experimenter name = Itsara Pracharoenwattana Experimenter phone = 0131 650 5316 Experimenter fax = 0131 650 5392 Experimenter department = Institute of Molecular Plant Sciences Experimenter institute = University of Edinburgh Experimenter address = Daniel Rutherford Building University of Edinburgh Experimenter address = The King's Buildings Experimenter address = Edinburgh Experimenter zip/postal_code = EH9 3JH Experimenter country = UK Keywords: genetic_modification_design
2007-01-08 | GSE5641 | GEO
Project description:Helf MJ, Fox BW, Artyukhin AB, Zhang YK, Schroeder FC (2021) Comparative metabolomics with Metaboseek reveals functions of peroxisomal alpha-oxidation in C. elegans
2021-07-26 | MSV000087885 | MassIVE
Project description:Augmenting regenerative hematopoietic stem cell self-renewal by intervening in peroxisomal β-oxidation
| PRJNA1248477 | ENA