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Subramani, Suresh. "PEX genes on the rise." Nature Genetics 15, no. 4 (April 1997): 331–33. http://dx.doi.org/10.1038/ng0497-331.
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Baker, A., W. Charlton, B. Johnson, E. Lopez-Huertas, J. Oh, I. Sparkes, and J. Thomas. "Biochemical and molecular approaches to understanding protein import into peroxisomes." Biochemical Society Transactions 28, no. 4 (August 1, 2000): 499–504. http://dx.doi.org/10.1042/bst0280499.
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Peroxisomes are eukaryotic organelles that perform diverse and variable functions. Although genetic studies in yeasts and mammals have identified approximately 20 genes (PEX genes) required for the biogenesis of this important organelle, biochemical studies of protein targeting and import have lagged behind and in many cases we have no idea of the function of the PEX gene products (peroxins). Using an import assay in vitro derived from sunflower cotyledon cells and recombinant proteins, we have obtained translocation intermediates on the peroxisome import pathway and are using cross-linking to identify interacting partners. We have also used antibodies raised against human PEX14 to inhibit the import of matrix proteins in this system. To obtain homologous antibodies for inhibition experiments, to immunoprecipitate cross-linked products and to enable us to study the import pathways of peroxins we have cloned and characterized plant orthologues of three PEX genes, PEX6, PEX10 and PEX14.
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Berner, Daniel, Ursula Hoja, Matthias Zenkel, James Julian Ross, Steffen Uebe, Daniela Paoli, Paolo Frezzotti, et al. "The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome." Human Molecular Genetics 28, no. 15 (April 15, 2019): 2531–48. http://dx.doi.org/10.1093/hmg/ddz075.
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AbstractLOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common non-coding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (odds ratio, OR = 0.63; P = 6.33 × 10−31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 [stimulated by retinoic acid (RA) receptor 6], apparently mediated by allele-specific binding of the transcription factor thyroid hormone receptor beta. We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven RA signaling pathway. siRNA-mediated downregulation of RA signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.
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Johnson, Monique A., Hans R. Waterham, Galyna P. Ksheminska, Liubov R. Fayura, Joan Lin Cereghino, Oleh V. Stasyk, Marten Veenhuis, Aleksander R. Kulachkovsky, Andrei A. Sibirny, and James M. Cregg. "Positive Selection of Novel Peroxisome Biogenesis-Defective Mutants of the Yeast Pichia pastoris." Genetics 151, no. 4 (April 1, 1999): 1379–91. http://dx.doi.org/10.1093/genetics/151.4.1379.
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Abstract We have developed two novel schemes for the direct selection of peroxisome-biogenesis-defective (pex) mutants of the methylotrophic yeast Pichia pastoris. Both schemes take advantage of our observation that methanol-induced pex mutants contain little or no alcohol oxidase (AOX) activity. AOX is a peroxisomal matrix enzyme that catalyzes the first step in the methanol-utilization pathway. One scheme utilizes allyl alcohol, a compound that is not toxic to cells but is oxidized by AOX to acrolein, a compound that is toxic. Exposure of mutagenized populations of AOX-induced cells to allyl alcohol selectively kills AOX-containing cells. However, pex mutants without AOX are able to grow. The second scheme utilizes a P. pastoris strain that is defective in formaldehyde dehydrogenase (FLD), a methanol pathway enzyme required to metabolize formaldehyde, the product of AOX. AOX-induced cells of fld1 strains are sensitive to methanol because of the accumulation of formaldehyde. However, fld1 pex mutants, with little active AOX, do not efficiently oxidize methanol to formaldehyde and therefore are not sensitive to methanol. Using these selections, new pex mutant alleles in previously identified PEX genes have been isolated along with mutants in three previously unidentified PEX groups.
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Tomczyk-Socha, Martyna, Wojciech Tomczak, and Anna Turno-Kręcicka. "The Importance of MicroRNA Expression in Pseudoexfoliation Syndrome." International Journal of Molecular Sciences 23, no. 21 (October 31, 2022): 13234. http://dx.doi.org/10.3390/ijms232113234.
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Pseudoexfoliation syndrome (PEX) is an important systemic disorder of the extracellular matrix, in which granular amyloid-like protein fibers accumulate in the anterior segment of the eyeball as well as in other organs. PEX is currently considered to be a multifactorial systemic disorder with genetic and environmental risk factors. The aim of this manuscript was to analyze miR expression in PEX. In recent years, an attempt has been made to investigate and describe the level of expression of selected miRs in PEX. Four polymorphisms of genes isolated from the blood that may be related to PEX were identified and miR-122-5p was found to be upregulated in patient blood. Furthermore, 18 miRs were identified with a statistically different expression in the aqueous humor. A significantly elevated expression of miR-125b was found in the anterior lens capsule, and four miRs were described, which may have a significant impact on the development of PEX. Regulatory miR molecules are gaining more and more importance in research aimed at identifying and isolating molecular markers related to the pathogenesis and prognosis of PEX, but further studies are needed.
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Kiel, Jan A. K. W., Marten Veenhuis, and Ida J. van der Klei. "PEX Genes in Fungal Genomes: Common, Rare or Redundant." Traffic 7, no. 10 (September 13, 2006): 1291–303. http://dx.doi.org/10.1111/j.1600-0854.2006.00479.x.
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Baes, Myriam, and Paul P. Van Veldhoven. "Generalised and conditional inactivation of Pex genes in mice." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1763, no. 12 (December 2006): 1785–93. http://dx.doi.org/10.1016/j.bbamcr.2006.08.018.
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Tomczyk-Socha, Martyna, Julia Kręcicka, Marta Misiuk-Hojło, and Anna Turno-Kręcicka. "MicroRNA Expression in Pseudoexfoliation Syndrome with the Use of Next-Generation Sequencing." Genes 13, no. 4 (March 25, 2022): 582. http://dx.doi.org/10.3390/genes13040582.
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Pseudoexfoliation syndrome (PEX) is a clinically important and biologically intriguing systemic disorder of the extracellular matrix. PEX etiopathogenesis was proved to be connected to multiple genes and other factors. However, the exact etiopathogenesis remains unknown. The aim of this study was to analyze miR expression in PEX using next-generation sequencing. An attempt was made to find the most commonly occurring miR in PEX, to evaluate miR that may have an essential role in the etiology of PEX syndrome. In addition, the correlation between the selected miRs’ expressions and age was investigated. Anterior lens capsules were obtained during cataract surgery. Next-generation sequencing was conducted on Illumina MiSeq. The average age was 68.2 years (with standard deviation +/− 6.92 years). Ten miRs with the highest level of expression represent approx. 95% of all readings. Four miRs with statistically significant differences in expression between groups have been distinguished: miR-671-3p, miR374a-5p, miR-1307-5p and miR-708-5p. The relationship between the most frequent miRs’ expressions and age has been evaluated and no correlation has been detected. In view of the above, it seems reasonable to examine the influence of miR on the biogenesis of PEX. Further studies on miR-671-3p, miR-374a-5p, miR-1307-5p and miR-708-5p expression in PEX are needed.
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Zhang, Hongji, Xiang Cheng, Meihong Deng, Allan Tsung, and Hai Huang. "Preoperative exercise therapy attenuates liver metastases following surgical stress by inducing Kupffer cells-mediated anti-tumor immunity." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 118.09. http://dx.doi.org/10.4049/jimmunol.208.supp.118.09.
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Abstract Introduction Resection of colorectal cancer hepatic metastases improves overall disease-free survival. Unfortunately, not all patients have a successful surgical outcome. Pre-operative exercise therapy (PEx) have been demonstrated to be beneficial in the prevention of post-operative complications. We hypothesize that PEx initially reverts pro-tumorigenic inflammatory responses following surgical stress and maintains an anti-tumor immune microenvironment through modulating Kupffer cells (KCs) with anti-tumor immunity. Methods 8W C57BL/6 mice were randomly divided into PEx and sedentary (Sed) groups, mice with PEx run on a motorized treadmill at a speed of 12.5 m/min for 60 min/day, 5 days/W for 4 weeks. 105 MC38 cells were injected directly through portal vein and surgical stress was subjected to partial hepatic ischemia and reperfusion model. Both hepatic and tumor CD45+ cells from PEx or Sed mice 3 W after IR were submitted for single-cell RNA sequencing (scRNA-seq). Results 4 weeks of PEx significantly reduces metastasis in the liver along 3 weeks after IR, compared with Sed controls. For the scRNA-seq, 11 cell lineages were identified and annotated according to the transcriptomic profile of feature genes expression. Surprisingly, discontinued 4-week-PEx still led to a significant transcriptomic shift in the KCs. 3 clusters from the entire KCs population were unique in PEx mice. In contrast, 2 Clusters were derived from Sed mice. PEx-relevant KCs are enriched in gene expression related to the anti-tumor phenotype, whereas Sed-relevant KCs are enriched in gene expression related to pro-tumor or immunosuppressive phenotype, which suggests that PEx modulates transcriptomic changes in KCs towards an anti-tumor phenotype. Supported by National Institutes of Health R01-CA214865-01 and R01-GM95566-06 to AT, National Institutes of Health R01-AI152044 to MD, and National Institutes of Health R01-GM137203 and Joseph A. Patrick Research Fellowship in Transplantation to HH.
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Zhang, Hongji, Xiang Cheng, Chengli Shen, Meihong Deng, Allan Tsung, and Hai Huang. "Abstract 2109: Preoperative exercise therapy attenuates the progression of liver metastases following surgical stress by inducing Kupffer cells-mediated anti-tumor trained immunity." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2109. http://dx.doi.org/10.1158/1538-7445.am2022-2109.
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Abstract Introduction: Colorectal cancer (CRC) is a devastating disease, causing mortality worldwide, with the majority of the patients dying from hepatic metastasis. Resection of hepatic metastases improves overall disease-free survival. Unfortunately, not all patients have a successful surgical outcome. Pre-operative exercise therapy (PEx) have been demonstrated to be beneficial in the prevention of post-operative complications. Trained immunity in myeloid cells leads to an aggravated long-term inflammatory phenotype upon a secondary stimulation, a process that results from orchestrated metabolic-epigenetic changes. We hypothesize that PEx initially reverts pro-tumorigenic inflammatory responses following surgical stress and maintains an anti-tumor immune microenvironment through modulating Kupffer cells (KCs) with anti-tumor immunity. Methods: 8-week C57BL/6 mice were randomly divided into PEx and sedentary (Sed) groups, mice with PEx run on a motorized treadmill at a speed of 12.5 m/min for 60 min/day, 5 days/week for 4 weeks. 105 MC38 cells were injected directly through portal vein and surgical stress was subjected to a model of partial hepatic ischemia and reperfusion. The tumor progression was determined by bioluminescent imaging weekly. Both hepatic and tumor CD45+ cells from PEx or Sed mice 3 weeks after IR were submitted for single-cell RNA sequencing (scRNA-seq). Results: 4 weeks of PEx significantly reduces metastasis in the liver along 3 weeks after IR, compared with Sed controls. For the scRNA-seq, 11 cell lineages (KCs, monocytes, neutrophils, DCs, TAMs, TANs, B cells, CD4+ T cells, CD8+ T cells, NK cells, and NKT cells) were identified and annotated according to the transcriptomic profile of feature genes expression. Surprisingly, discontinued 4-week-PEx still led to a significant transcriptomic shift in the KCs. 3 clusters from the entire KCs population were unique in PEx mice. In contrast, 2 Clusters were derived from Sed mice. PEx-relevant KCs are enriched in gene expression related to the anti-tumor phenotype, whereas Sed-relevant KCs are enriched in gene expression related to pro-tumor or immunosuppressive phenotype, which suggests that PEx modulates transcriptomic changes in KCs towards an anti-tumor phenotype. Furthermore, with our established ex vivo trained immunity assay, we observe a clear induction of trained immunity in PEx-KCs when co-cultured with MC38 tumor cells, with noticeably higher levels of anti-tumor cytokines interferon (IFN)-γ and TNF-α compared to Sed-KCs. Summary: Our study is one of the first to show that PEx alters the hepatic immune microenvironment by shifting KC to a tumoricidal phenotype. This work offers a rationale for PEx for cancer patients undergoing liver surgery thereby decreasing post-operative metastases and morbidity. Citation Format: Hongji Zhang, Xiang Cheng, Chengli Shen, Meihong Deng, Allan Tsung, Hai Huang. Preoperative exercise therapy attenuates the progression of liver metastases following surgical stress by inducing Kupffer cells-mediated anti-tumor trained immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2109.
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Smith, Jennifer J., Marcello Marelli, Rowan H. Christmas, Franco J. Vizeacoumar, David J. Dilworth, Trey Ideker, Timothy Galitski, Krassen Dimitrov, Richard A. Rachubinski, and John D. Aitchison. "Transcriptome profiling to identify genes involved in peroxisome assembly and function." Journal of Cell Biology 158, no. 2 (July 22, 2002): 259–71. http://dx.doi.org/10.1083/jcb.200204059.
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Yeast cells were induced to proliferate peroxisomes, and microarray transcriptional profiling was used to identify PEX genes encoding peroxins involved in peroxisome assembly and genes involved in peroxisome function. Clustering algorithms identified 224 genes with expression profiles similar to those of genes encoding peroxisomal proteins and genes involved in peroxisome biogenesis. Several previously uncharacterized genes were identified, two of which, YPL112c and YOR084w, encode proteins of the peroxisomal membrane and matrix, respectively. Ypl112p, renamed Pex25p, is a novel peroxin required for the regulation of peroxisome size and maintenance. These studies demonstrate the utility of comparative gene profiling as an alternative to functional assays to identify genes with roles in peroxisome biogenesis.
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Shi, Hengzhi, Xiaocui Huang, Xueqiu Chen, Yi Yang, Zhao Wang, Yimin Yang, Fei Wu, et al. "Acyl-CoA oxidase ACOX-1 interacts with a peroxin PEX-5 to play roles in larval development of Haemonchus contortus." PLOS Pathogens 17, no. 7 (July 16, 2021): e1009767. http://dx.doi.org/10.1371/journal.ppat.1009767.
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Hypobiosis (facultative developmental arrest) is the most important life-cycle adaptation ensuring survival of parasitic nematodes under adverse conditions. Little is known about such survival mechanisms, although ascarosides (ascarylose with fatty acid-derived side chains) have been reported to mediate the formation of dauer larvae in the free-living nematode Caenorhabditis elegans. Here, we investigated the role of a key gene acox-1, in the larval development of Haemonchus contortus, one of the most important parasitic nematodes that employ hypobiosis as a routine survival mechanism. In this parasite, acox-1 encodes three proteins (ACOXs) that all show a fatty acid oxidation activity in vitro and in vivo, and interact with a peroxin PEX-5 in peroxisomes. In particular, a peroxisomal targeting signal type1 (PTS1) sequence is required for ACOX-1 to be recognised by PEX-5. Analyses on developmental transcription and tissue expression show that acox-1 is predominantly expressed in the intestine and hypodermis of H. contortus, particularly in the early larval stages in the environment and the arrested fourth larval stage within host animals. Knockdown of acox-1 and pex-5 in parasitic H. contortus shows that these genes play essential roles in the post-embryonic larval development and likely in the facultative arrest of this species. A comprehensive understanding of these genes and the associated β-oxidation cycle of fatty acids should provide novel insights into the developmental regulation of parasitic nematodes, and into the discovery of novel interventions for species of socioeconomic importance.
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Lin-Cereghino, Geoffrey Paul, Laurie Godfrey, Bernard J. de la Cruz, Sabrina Johnson, Samone Khuongsathiene, Ilya Tolstorukov, Mingda Yan, et al. "Mxr1p, a Key Regulator of the Methanol Utilization Pathway and Peroxisomal Genes in Pichia pastoris." Molecular and Cellular Biology 26, no. 3 (February 1, 2006): 883–97. http://dx.doi.org/10.1128/mcb.26.3.883-897.2006.
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ABSTRACT Growth of the yeast Pichia pastoris on methanol induces the expression of genes whose products are required for its metabolism. Three of the methanol pathway enzymes are located in an organelle called the peroxisome. As a result, both methanol pathway enzymes and proteins involved in peroxisome biogenesis (PEX proteins) are induced in response to this substrate. The most highly regulated of these genes is AOX1, which encodes alcohol oxidase, the first enzyme of the methanol pathway, and a peroxisomal enzyme. To elucidate the molecular mechanisms responsible for methanol regulation, we identify genes required for the expression of AOX1. Mutations in one gene, named MXR1 (methanol expression regulator 1), result in strains that are unable to (i) grow on the peroxisomal substrates methanol and oleic acid, (ii) induce the transcription of AOX1 and other methanol pathway and PEX genes, and (iii) form normal-appearing peroxisomes in response to methanol. MXR1 encodes a large protein with a zinc finger DNA-binding domain near its N terminus that has similarity to Saccharomyces cerevisiae Adr1p. In addition, Mxr1p is localized to the nucleus in cells grown on methanol or other gluconeogenic substrates. Finally, Mxr1p specifically binds to sequences upstream of AOX1. We conclude that Mxr1p is a transcription factor that is necessary for the activation of many genes in response to methanol. We propose that MXR1 is the P. pastoris homologue of S. cerevisiae ADR1 but that it has gained new functions and lost others through evolution as a result of changes in the spectrum of genes that it controls.
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Ruprich-Robert, Gwenaël, Véronique Berteaux-Lecellier, Denise Zickler, Arlette Panvier-Adoutte, and Marguerite Picard. "Identification of Six Loci in Which Mutations Partially Restore Peroxisome Biogenesis and/or Alleviate the Metabolic Defect of pex2 Mutants in Podospora." Genetics 161, no. 3 (July 1, 2002): 1089–99. http://dx.doi.org/10.1093/genetics/161.3.1089.
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Abstract Peroxins (PEX) are proteins required for peroxisome biogenesis. Mutations in PEX genes cause lethal diseases in humans, metabolic defects in yeasts, and developmental disfunctions in plants and filamentous fungi. Here we describe the first large-scale screening for suppressors of a pex mutation. In Podospora anserina, pex2 mutants exhibit a metabolic defect [inability to grow on medium containing oleic acid (OA medium) as sole carbon source] and a developmental defect (inability to differentiate asci in homozygous crosses). Sixty-three mutations able to restore growth of pex2 mutants on OA medium have been analyzed. They fall in six loci (suo1 to suo6) and act as dominant, allele-nonspecific suppressors. Most suo mutations have pleiotropic effects in a pex2+ background: formation of unripe ascospores (all loci except suo5 and suo6), impaired growth on OA medium (all loci except suo4 and suo6), or sexual defects (suo4). Using immunofluorescence and GFP staining, we show that peroxisome biogenesis is partially restored along with a low level of ascus differentiation in pex2 mutant strains carrying either the suo5 or the suo6 mutations. The data are discussed with respect to β-oxidation of fatty acids, peroxisome biogenesis, and cell differentiation.
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Gasińska, Karolina, Marcin Czop, Ewa Kosior-Jarecka, Dominika Wróbel-Dudzińska, Janusz Kocki, and Tomasz Żarnowski. "Small Nucleolar RNAs in Pseudoexfoliation Glaucoma." Cells 11, no. 17 (September 2, 2022): 2738. http://dx.doi.org/10.3390/cells11172738.
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Small nucleolar RNAs (snoRNAs) are small non-coding regulatory RNAs that have been investigated extensively in recent years. However, the relationship between snoRNA and glaucoma is still unknown. This study aims to analyze the levels of snoRNA expression in the aqueous humor (AH) of patients with pseudoexfoliation glaucoma (PEXG) compared to a control group and identify hypothetical snoRNA-dependent mechanisms contributing to PEXG. The AH was obtained from eighteen Caucasian patients, comprising nine PEXG and nine age-matched control patients. RNA was isolated, and a microarray system was used to determine the snoRNA expression profiles. Functional and enrichment analyses were performed. We identified seven snoRNAs, SNORD73B, SNORD58A, SNORD56, SNORA77, SNORA72, SNORA64, and SNORA32, in the AH of the PEXG and control group patients. Five snoRNAs showed statistically significantly lower expression in the PEXG group, and two snoRNAs had statistically significantly higher expression in the PEXG group compared to the control group. In addition, we identified two factors—CACNB3 for SNORA64 and TMEM63C for SNORA32, similar to PEX-related genes (CACNA1A and TMEM136). The enrichment analysis for four genes targeted by snoRNAs revealed possible mechanisms associated with glaucoma and/or PEX, but the direct role of snoRNAs in these biological processes was not proven.
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Oliveira, Samilly, Elias Machado, Fabricio Fóla, Zumira Aparecida Carneiro, and Charles Marques Lourenço. "Uso de canabidiol como terapia adjuvante em paciente com síndrome de Zellweger: relato de caso." Medicina (Ribeirão Preto) 53, no. 3 (October 14, 2020): 321–26. http://dx.doi.org/10.11606/issn.2176-7262.v53i3p321-326.
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Também denominada síndrome cerebrohepatorenal, a síndrome de Zellweger é uma doença autossômica recessiva rara, pertencente ao espectro de erros inatos do metabolismo que afetam os peroxissomos. São causados principalmente por mutações em qualquer um dos 14 genes PEX diferentes que codificam para proteínas envolvidas na montagem do peroxissoma, sendo a mais comum do PEX1. O quadro clínico geralmente é observado no período neonatal e primeira infância, incluindo alterações faciais, hipotonia profunda e ausência de reflexos neonatais, além de disfagia, disfunção hepática e convulsões. O diagnóstico é feito a partir da clínica e testes bioquímicos e confirmados pela visualização da mutação em um dos 14 genes PEX. Como não há tratamento específico, é feito tratamento sintomático. Nosso paciente masculino de 1 ano e 9 meses apresentou a hipotonia congênita como sintoma marcante, além de crises convulsivas recorrentes logo após o nascimento. Evoluiu com necessidade de gastrostomia e estagnação de marcos neuromotores. O diagnóstico foi confirmado aos seis meses, através da dosagem de ácidos graxos de cadeia longa. Crises convulsivas evoluíram de maneira refratária a diversos anticonvulsivantes e com elevada frequência diária, por isso iniciamos canabidiol (CBD-RSHO GOLD) por via enteral que reduziu significantemente as crises. Não há tratamento definitivo para esta enfermidade, sendo importante tratamento sintomático das crises convulsivas e terapias de reabilitação, nesse caso, o uso de (CBD- RSHO GOLD) provocou uma redução de 92% na frequência de crises diárias do paciente. No entanto, não é possível concluir, ainda, melhoras em outros sinais e sintomas.
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Garikapati, Vannuruswamy, Claudia Colasante, Eveline Baumgart-Vogt, and Bernhard Spengler. "Sequential lipidomic, metabolomic, and proteomic analyses of serum, liver, and heart tissue specimens from peroxisomal biogenesis factor 11α knockout mice." Analytical and Bioanalytical Chemistry 414, no. 6 (January 27, 2022): 2235–50. http://dx.doi.org/10.1007/s00216-021-03860-0.
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AbstractPeroxisomes are versatile single membrane-enclosed cytoplasmic organelles, involved in reactive oxygen species (ROS) and lipid metabolism and diverse other metabolic processes. Peroxisomal disorders result from mutations in Pex genes-encoded proteins named peroxins (PEX proteins) and single peroxisomal enzyme deficiencies. The PEX11 protein family (α, β, and γ isoforms) plays an important role in peroxisomal proliferation and fission. However, their specific functions and the metabolic impact caused by their deficiencies have not been precisely characterized. To understand the systemic molecular alterations caused by peroxisomal defects, here we utilized untreated peroxisomal biogenesis factor 11α knockout (Pex11α KO) mouse model and performed serial relative-quantitative lipidomic, metabolomic, and proteomic analyses of serum, liver, and heart tissue homogenates. We demonstrated significant specific changes in the abundances of multiple lipid species, polar metabolites, and proteins and dysregulated metabolic pathways in distinct biological specimens of the Pex11α KO adult mice in comparison to the wild type (WT) controls. Overall, the present study reports comprehensive semi-quantitative molecular omics information of the Pex11α KO mice, which might serve in the future as a reference for a better understanding of the roles of Pex11α and underlying pathophysiological mechanisms of peroxisomal biogenesis disorders. Graphical abstract
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Havali, Cengiz, Sevil Dorum, Yılmaz Akbaş, Orhan Görükmez, and Tugba Hirfanoglu. "Two different missense mutations of PEX genes in two similar patients with severe Zellweger syndrome: an argument on the genotype-phenotype correlation." Journal of Pediatric Endocrinology and Metabolism 33, no. 3 (March 26, 2020): 437–41. http://dx.doi.org/10.1515/jpem-2019-0194.
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AbstractBackgroundPeroxisomal biogenesis disorders (PBDs) include a miscellaneous group of diseases which cause serious multisystem disease. Mutations of 13 different PEX genes lead to PBDs including Zellweger syndrome (ZS). Different types of mutations of PEX1 and PEX10 genes are correlated with broad-range phenotypes of PBDs.Case presentationPatient 1 is a 4-month-old boy who was affected by myoclonic seizures, poor oral feeding since birth. The patient was hypotonic and had hepatosplenomegaly. Patient 2 is a 2-month-old boy who presented with decreased movement, severe hypotonia and failure to thrive. The laboratory studies of the patients revealed increased plasma very-long-chain fatty acids (VLCFAs). The genetic analyses of patient 1 demonstrated the first homozygous missense mutation in the PEX10 gene. A novel homozygous missense mutation was found in the PEX1 gene in patient 2.ConclusionsThis report highlights that the detected homozygous missense mutations of PEX10 and PEX1 genes and the substitutions of specific amino acids lead to the severe form of PBDs.
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Depreter, M., J. Vandesompele, M. Espeel, F. Speleman, and F. Roels. "Modulation of the peroxisomal gene expression pattern by dehydroepiandrosterone and vitamin D: therapeutic implications." Journal of Endocrinology 175, no. 3 (December 1, 2002): 779–92. http://dx.doi.org/10.1677/joe.0.1750779.
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Peroxisomes are ubiquitous organelles required for several metabolic functions. Their dysfunction is responsible for a group of human inherited disorders. In the search for endogenous factors regulating the peroxisomal compartment in normal liver, we treated female rats with dehydroepiandrosterone (DHEA) and 25-hydroxycholecalciferol for 1 and 6 days. Relative transcription levels of 39 selected genes were evaluated by real-time quantitative RT-PCR analysis. Catalase (peroxisomal marker)-specific activity was assayed in total liver homogenate and peroxisomes were visualized by catalase localization. DHEA induced peroxisome proliferation and raised catalase specific activity. Expression levels of 16 (of which 11 were peroxisomal) genes were altered. Pex 11, acyl-CoA oxidase,l - andd -multifunctional enzyme, thiolase 1, phytanoyl-CoA hydroxylase, 70 kDa peroxisomal membrane protein and very long chain acyl-CoA synthetase were upregulated, three others were downregulated. Vitamin D caused downregulation of six genes. Administration of vitamin D to peroxisomal disorder patients may be contraindicated. The adrenocortical hormone DHEA is a potential natural regulator of the peroxisomal compartment. Its therapeutic use in X-linked adrenoleukodystrophy, some other beta-oxidation defects and classical Refsum should be considered.
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Ferrer, Francisco, Marisa Roldão, Cátia Figueiredo, and Karina Lopes. "Atypical Hemolytic Uremic Syndrome after ChAdOx1 nCoV-19 Vaccination in a Patient with Homozygous CFHR3/CFHR1 Gene Deletion." Nephron 146, no. 2 (November 1, 2021): 185–89. http://dx.doi.org/10.1159/000519461.
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Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) affecting the kidneys. Compared with typical HUS due to an infection from shiga toxin-producing <i>Escherichia coli</i>, atypical HUS involves a genetic or acquired dysregulation of the complement alternative pathway. In the presence of a mutation in a complement gene, a second trigger is often necessary for the development of the disease. We report a case of a 54-year-old female, with a past medical history of pulmonary tuberculosis, who was admitted to the emergency service with general malaise and reduction in urine output, 5 days after vaccination with ChAdOx1 nCoV-19. Laboratory results revealed microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Given the clinical picture of TMA, plasma exchange (PEX) was immediately started, along with hemodialysis. Complementary laboratory workup for TMA excluded thrombotic thrombocytopenic purpura and secondary causes. Complement study revealed normal levels of factors H, B, and I, normal activity of the alternate pathway, and absence of anti-factor H antibodies. Genetic study of complement did not show pathogenic variants in the 12 genes analyzed, but revealed a deletion in gene CFHR3/CFHR1 in homozygosity. Our patient completed 10 sessions of PEX, followed by eculizumab, with both clinical and laboratorial improvement. Actually, given the short time lapse between vaccination with ChAdOx1 nCoV-19 and the clinical manifestations, we believe that vaccine was the trigger for the presentation of aHUS in this particular case.
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Tam, Yuen Yi C., and Richard A. Rachubinski. "Yarrowia lipolyticaCells Mutant for thePEX24Gene Encoding a Peroxisomal Membrane Peroxin Mislocalize Peroxisomal Proteins and Accumulate Membrane Structures Containing Both Peroxisomal Matrix and Membrane Proteins." Molecular Biology of the Cell 13, no. 8 (August 2002): 2681–91. http://dx.doi.org/10.1091/mbc.e02-02-0117.
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Peroxins are proteins required for peroxisome assembly and are encoded by the PEX genes. Functional complementation of the oleic acid–nonutilizing strain mut1-1 of the yeastYarrowia lipolytica has identified the novel gene,PEX24. PEX24 encodes Pex24p, a protein of 550 amino acids (61,100 Da). Pex24p is an integral membrane protein of peroxisomes that exhibits high sequence homology to two hypothetical proteins encoded by the open reading frames YHR150W andYDR479C of the Saccharomyces cerevisiaegenome. Pex24p is detectable in wild-type cells grown in glucose-containing medium, and its levels are significantly increased by incubation of cells in oleic acid–containing medium, the metabolism of which requires intact peroxisomes. pex24 mutants are compromised in the targeting of both matrix and membrane proteins to peroxisomes. Although pex24 mutants fail to assemble functional peroxisomes, they do harbor membrane structures that contain subsets of peroxisomal proteins.
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Mandala, Eudokia M., Spyridon Gkiouzepas, Efstratios Kasimatis, Christos Lafaras, Parthenis Chalevas, Konstantina Tsioni, Krystallia Kyrka, et al. "Pregnancy-Associated Atypical Hemolytic Uremic Syndrome (aHUS), Treated with Eculizumab." Blood 124, no. 21 (December 6, 2014): 5019. http://dx.doi.org/10.1182/blood.v124.21.5019.5019.
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Abstract Introduction:aHUS is a life-threatening, chronic, progressive disease of complement mediated thrombotic microangiopathy (TMA), commonly associatedwith pregnancy, 10-20% of all cases (P-aHUS), that usually occurs in late pregnancy and postpartum, primiparous women. Plasma exchange (PEX) may transiently maintain hematologic parameters, but does not treat the underlying systemic disease. Clinical studies have shown excellent effectiveness of eculizumab (Soliris®), the only complement inhibitor, used in PNH treatment. In 2011, eculizumab was approved for the treatment of aHUS. We report the 1st case of aHUS treated with eculizumab, in Greece, which was pregnancy related. A 29 years old female, on the 16th week of gestation was referred, due to anemia (Hgb 6.9 g/dL) and thrombocytopenia (plt 78.000/μL). Family history: father with renal transplantation. Clinical examination: no abnormal findings. Laboratory exams: coagulation tests normal, low fibrinogen, 5-6 schistocytes/hpf, retics 12%, normal liver function, LDH 975 IU/L (normal range, nr 0-248), inDBil 2,5 mg/dl, ESR 41, CRP negative. Renal function was mildly deteriorated, urea 50 mg/dL, creatinine 1.3 mg/dL, proteinurea (urine protein 1 g/24h). The patient was diagnosed with pregnancy associated TMA and underwent daily PEX plus steroids. Partial response for the first 3-4 days. IVIgG was added. Rapid relapse with fall in Hgb, Hct, plt, schistocytes 6-8/hpf, decrease in fibrinogen, LDH and inDBil elevation. Pregnancy was terminated on the 8th day of hospitalization, by uterine section. She was transferred to the ICU: diffuse bleeding from operative wound/drains. She had daily PEX and RBCs, PLTs, FFPs, CPs transfusions, schistocytes 12-18/hpf. Rituximab 375 mg/m2/5 days × 5 cycles, begun 2 weeks after PEX initiation. Diagnostic testing: antiphospholipid antibodies (PTTLa, anti-B2GPI, ACAs) negative, APC-R positive, FVL heterozygous, virology tests (anti-HIV, HBsAg, anti-HCV) negative, immunology tests (ANAs, anti-ds-DNA, anti-ENAs) negative, stool cultures negative, Verotoxin/E. Coli 0157 antibodies negative, PNH test by high sensitivity flow cytometrynegative, complement levels at the lower normal, normal ADAMTS13 activity. Post-operatively, daily PEX and RBCs, FFPs transfusions, replenish fibrinogen. Refractory arterial hypertension (furosemide, clonidine, amlodipine). Severe kidney involvement (urine protein 14-44g/24h). Laboratoryresults: Hgb 6.6 mg/dL, plt 52.000/μL, creatinine 1.04 mg/dL, inDBil 2 mg/dL, LDH1100 IU/L. So, the patient showing no response to treatments, was in poor clinical condition, multitransfused, with whole body edema. The diagnosisof aHUS was confirmed by clinical and laboratory findings. The patient was vaccinated against Neisseria meningitidis with tetravalent conjugated, serogroups A, C, W-135, and Y (Menveo®) and serogroup Β strains (Bexsero®) and eculizumab was started,on day 47, in the suggested protocol, 900 mg/week × 4 weeks, 1200 mg, week 5, following maintenance with 1200 mg/2 weeks, indefinitely. She experienced immediate “weaning” from PEX withrapid and stable improvement of all pathological parameters andgradual resolution of proteinuria. Recent laboratory tests: normal blood counts, LDH 161 IU/L, creatinine 0.7 mg/dL, urine protein 1 g/24h. Renal biopsy performed after remission identified morphological (segmental double contour of glomerular basic membrane, focal segmental glomerular sclerosis and mesangiolysis) and immunohistochemical (subendothelial, subepithelial and mesangial IgM, C3d, C1q deposition), all consistent with TMA, HUS type. Molecular genetics by NG Sequencing for CFH, MCP, CFB, C3, CFI, THBD, CFHR5, ADAMTS13, C6A, C9B, C9, CFD and DGKE genes, identified no mutations known as a cause for aHUS, by now. However, aHUS is a genetically complex and heterogeneous disorder. Conclusions: Therapy with eculizumab was life saving in our case, inducing rapid response of all active TMA markers and renal involvement recovery. Only 16% of P-aHUS occurs during the 2nd semester of pregnancy, as in our case. Multiple risk factors during pregnancy may trigger an acute episode of TMA in predisposed women and a contributing effect of hereditary thrombophilia plays a role in the pathophysiology of aHUS. The co-existence of hereditary thrombophilia, FVL heterozygous, might have played a role in the aHUS presentation during pregnancy, in our patient. Disclosures No relevant conflicts of interest to declare.
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SZILARD, Rachel K., and Richard A. RACHUBINSKI. "Tetratricopeptide repeat domain of Yarrowia lipolytica Pex5p is essential for recognition of the type 1 peroxisomal targeting signal but does not confer full biological activity on Pex5p." Biochemical Journal 346, no. 1 (February 8, 2000): 177–84. http://dx.doi.org/10.1042/bj3460177.
Full textAbstract:
Peroxins are proteins required for peroxisome assembly and are encoded by the PEX genes. The Yarrowia lipolytica pex5-1 mutant fails to import a subset of peroxisomal matrix proteins, including those with a type 1 peroxisomal targeting signal (PTS1). Pex5p family members interact with a PTS1 through their characteristic tetratricopeptide repeat (TPR) domain. We used binding assays in vitro to investigate the nature of the association of Y. lipolytica Pex5p (YlPex5p) with the PTS1 signal. A purified recombinant YlPex5p fusion protein interacted specifically, directly and autonomously with a protein terminating in a PTS1. Wild-type YlPex5p translated in vitro recognized functional PTS1s specifically. This activity is abrogated by the substitution of an aspartic residue for a conserved glycine residue in the TPR domain (G455D) of YlPex5p encoded by the pex5-1 allele. Deletion analysis demonstrated that an intact TPR domain of YlPex5p is necessary but not sufficient for both interaction with a PTS1 and functional complementation of a strain lacking YlPex5p.
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Smith, J. J., R. K. Szilard, M. Marelli, and R. A. Rachubinski. "The peroxin Pex17p of the yeast Yarrowia lipolytica is associated peripherally with the peroxisomal membrane and is required for the import of a subset of matrix proteins." Molecular and Cellular Biology 17, no. 5 (May 1997): 2511–20. http://dx.doi.org/10.1128/mcb.17.5.2511.
Full textAbstract:
PEX genes encode peroxins, which are required for the biogenesis of peroxisomes. The Yarrowia lipolytica PEX17 gene encodes the peroxin Pex17p, which is 671 amino acids in length and has a predicted molecular mass of 75,588 Da. Pex17p is peripherally associated with the peroxisomal membrane. The carboxyl-terminal tripeptide, Gly-Thr-Leu, of Pex17p is not necessary for its targeting to peroxisomes. Synthesis of Pex17p is low in cells grown in glucose-containing medium and increases after the cells are shifted to oleic acid-containing medium. Cells of the pex17-1 mutant, the original mutant strain, and the pex17-KA mutant, a strain in which most of the PEX17 gene is deleted, fail to form normal peroxisomes but instead contain numerous large, multimembraned structures. The import of peroxisomal matrix proteins in these mutants is selectively impaired. This selective import is not a function of the nature of the peroxisomal targeting signal. We suggest a regulatory role for Pex17p in the import of a subset of matrix proteins into peroxisomes.
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SUBRAMANI, SURESH. "Components Involved in Peroxisome Import, Biogenesis, Proliferation, Turnover, and Movement." Physiological Reviews 78, no. 1 (January 1, 1998): 171–88. http://dx.doi.org/10.1152/physrev.1998.78.1.171.
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Subramani, Suresh. Components Involved in Peroxisome Import, Biogenesis, Proliferation, Turnover, and Movement. Physiol. Rev. 78: 171–188, 1998. — In the decade that has elapsed since the discovery of the first peroxisomal targeting signal (PTS), considerable information has been obtained regarding the mechanism of protein import into peroxisomes. The PTSs responsible for the import of matrix and membrane proteins to peroxisomes, the receptors for several of these PTSs, and docking proteins for the PTS1 and PTS2 receptors are known. Many peroxins involved in peroxisomal protein import and biogenesis have been characterized genetically and biochemically. These studies have revealed important new insights regarding the mechanism of protein translocation across the peroxisomal membrane, the conservation of PEX genes through evolution, the role of peroxins in fatal human peroxisomal disorders, and the biogenesis of the organelle. It is clear that peroxisomal protein import and biogenesis have many features unique to this organelle alone. More recent studies on peroxisome degradation, division, and movement highlight newer aspects of the biology of this organelle that promise to be just as exciting and interesting as import and biogenesis.
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Demaret, Tanguy, Jonathan Evraerts, Joachim Ravau, Martin Roumain, Giulio G. Muccioli, Mustapha Najimi, and Etienne M. Sokal. "High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in Pex1-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment." Cells 10, no. 1 (December 30, 2020): 40. http://dx.doi.org/10.3390/cells10010040.
Full textAbstract:
Genetic alterations in PEX genes lead to peroxisome biogenesis disorder. In humans, they are associated with Zellweger spectrum disorders (ZSD). No validated treatment has been shown to modify the dismal natural history of ZSD. Liver transplantation (LT) improved clinical and biochemical outcomes in mild ZSD patients. Hepatocyte transplantation (HT), developed to overcome LT limitations, was performed in a mild ZSD 4-year-old child with encouraging short-term results. Here, we evaluated low dose (12.5 million hepatocytes/kg) and high dose (50 million hepatocytes/kg) syngeneic male HT via intrasplenic infusion in the Pex1-G844D NMRI mouse model which recapitulates a mild ZSD phenotype. HT was feasible and safe in growth retarded ZSD mice. Clinical (weight and food intake) and biochemical parameters (very long-chain fatty acids, abnormal bile acids, etc.) were in accordance with ZSD phenotype but they were not robustly modified by HT. As expected, one third of the infused cells were detected in the liver 24 h post-HT. No liver nor spleen microchimerism was detected after 7, 14 and 30 days. Future optimizations are required to improve hepatocyte engraftment in Pex1-G844D NMRI mouse liver. The mouse model exhibited the robustness required for ZSD liver-targeted therapies evaluation.
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Min, Kyunghun, Hokyoung Son, Jungkwan Lee, Gyung Ja Choi, Jin-Cheol Kim, and Yin-Won Lee. "Peroxisome Function Is Required for Virulence and Survival of Fusarium graminearum." Molecular Plant-Microbe Interactions® 25, no. 12 (December 2012): 1617–27. http://dx.doi.org/10.1094/mpmi-06-12-0149-r.
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Peroxisomes are organelles that are involved in a number of important cellular metabolic processes, including the β-oxidation of fatty acids, biosynthesis of secondary metabolites, and detoxification of reactive oxygen species (ROS). In this study, the role of peroxisomes was examined in Fusarium graminearum by targeted deletion of three genes (PEX5, PEX6, and PEX7) encoding peroxin (PEX) proteins required for peroxisomal protein import. PEX5 and PEX7 deletion mutants were unable to localize the fluorescently tagged peroxisomal targeting signal type 1 (PTS1)- and PTS2-containing proteins to peroxisomes, respectively, whereas the PEX6 mutant failed to localize both fluorescent proteins. Deletion of PEX5 and PEX6 resulted in retarded growth on long-chain fatty acids and butyrate, while the PEX7 deletion mutants utilized fatty acids other than butyrate. Virulence on wheat heads was greatly reduced in the PEX5 and PEX6 deletion mutants, and they were defective in spreading from inoculated florets to the adjacent spikelets through rachis. Deletion of PEX5 and PEX6 dropped survivability of aged cells in planta and in vitro due to the accumulation of ROS followed by necrotic cell death. These results demonstrate that PTS1-dependent peroxisomal protein import mediated by PEX5 and PEX6 are critical to virulence and survival of F. graminearum.
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Lipiński, Patryk, Piotr Stawiński, Małgorzata Rydzanicz, Maria Wypchło, Rafał Płoski, Teresa Joanna Stradomska, Elżbieta Jurkiewicz, et al. "Mild Zellweger syndrome due to functionally confirmed novel PEX1 variants." Journal of Applied Genetics 61, no. 1 (October 18, 2019): 87–91. http://dx.doi.org/10.1007/s13353-019-00523-w.
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Abstract Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of 13 PEX genes. The broad clinical heterogeneity especially in late-onset presenting patients and a mild phenotype complicates and delays the diagnostic process. Here, we report a case of mild ZSD, due to novel PEX1 variants. The patient presented with an early hearing loss, bilateral cataracts, and leukodystrophy on magnetic resonance (MR) images. Normal results of serum very-long-chain fatty acids (VLCFA) and phytanic acid were found. Molecular diagnostics were performed to uncover the etiology of the clinical phenotype. Using whole exome sequencing, there have been found two variants in the PEX1 gene—c.3450T>A (p.Cys1150*) and c.1769T>C (p.Leu590Pro). VLCFA measurement in skin fibroblasts and C26:0-lysoPC in dried blood spot therefore was performed. Both results were in line with the diagnosis of ZSD. To conclude, normal results of routine serum VLCFA and branched-chain fatty acid measurement do not exclude mild forms of ZSD. The investigation of C26:0-lysoPC should be included in the diagnostic work-up in patients with cataract, hearing loss, and leukodystrophy on MR images suspected to suffer from ZSD.
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Birschmann, Ingvild, An K. Stroobants, Marlene van den Berg, Antje Schäfer, Katja Rosenkranz, Wolf-H. Kunau, and Henk F. Tabak. "Pex15p of Saccharomyces cerevisiae Provides a Molecular Basis for Recruitment of the AAA Peroxin Pex6p to Peroxisomal Membranes." Molecular Biology of the Cell 14, no. 6 (June 2003): 2226–36. http://dx.doi.org/10.1091/mbc.e02-11-0752.
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The gene products (peroxins) of at least 29 PEX genes are known to be necessary for peroxisome biogenesis but for most of them their precise function remains to be established. Here we show that Pex15p, an integral peroxisomal membrane protein, in vivo and in vitro binds the AAA peroxin Pex6p. This interaction functionally interconnects these two hitherto unrelated peroxins. Pex15p provides the mechanistic basis for the reversible targeting of Pex6p to peroxisomal membranes. We could demonstrate that the N-terminal part of Pex6p contains the binding site for Pex15p and that the two AAA cassettes D1 and D2 of Pex6p have opposite effects on this interaction. A point mutation in the Walker A motif of D1 (K489A) decreased the binding of Pex6p to Pex15p indicating that the interaction of Pex6p with Pex15p required binding of ATP. Mutations in Walker A (K778A) and B (D831Q) motifs of D2 abolished growth on oleate and led to a considerable larger fraction of peroxisome bound Pex6p. The nature of these mutations suggested that ATP-hydrolysis is required to disconnect Pex6p from Pex15p. On the basis of these results, we propose that Pex6p exerts at least part of its function by an ATP-dependent cycle of recruitment and release to and from Pex15p.
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Woodward, Andrew W., and Bonnie Bartel. "The Arabidopsis Peroxisomal Targeting Signal Type 2 Receptor PEX7 Is Necessary for Peroxisome Function and Dependent on PEX5." Molecular Biology of the Cell 16, no. 2 (February 2005): 573–83. http://dx.doi.org/10.1091/mbc.e04-05-0422.
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Plant peroxisomal proteins catalyze key metabolic reactions. Several peroxisome biogenesis PEROXIN (PEX) genes encode proteins acting in the import of targeted proteins necessary for these processes into the peroxisomal matrix. Most peroxisomal matrix proteins bear characterized Peroxisomal Targeting Signals (PTS1 or PTS2), which are bound by the receptors PEX5 or PEX7, respectively, for import into peroxisomes. Here we describe the isolation and characterization of an Arabidopsis peroxin mutant, pex7-1, which displays peroxisome-defective phenotypes including reduced PTS2 protein import. We also demonstrate that the pex5-1 PTS1 receptor mutant, which contains a lesion in a domain conserved among PEX7-binding proteins from various organisms, is defective not in PTS1 protein import, but rather in PTS2 protein import. Combining these mutations in a pex7-1 pex5-1 double mutant abolishes detectable PTS2 protein import and yields seedlings that are entirely sucrose-dependent for establishment, suggesting a severe block in peroxisomal fatty acid β-oxidation. Adult pex7-1 pex5-1 plants have reduced stature and bear abnormally shaped seeds, few of which are viable. The pex7-1 pex5-1 seedlings that germinate have dramatically fewer lateral roots and often display fused cotyledons, phenotypes associated with reduced auxin response. Thus PTS2-directed peroxisomal import is necessary for normal embryonic development, seedling establishment, and vegetative growth.
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Bülow, Margret H., Christian Wingen, Deniz Senyilmaz, Dominic Gosejacob, Mariangela Sociale, Reinhard Bauer, Heike Schulze, et al. "Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants." Molecular Biology of the Cell 29, no. 4 (February 15, 2018): 396–407. http://dx.doi.org/10.1091/mbc.e17-08-0535.
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Inherited peroxisomal biogenesis disorders (PBDs) are characterized by the absence of functional peroxisomes. They are caused by mutations of peroxisomal biogenesis factors encoded by Pex genes, and result in childhood lethality. Owing to the many metabolic functions fulfilled by peroxisomes, PBD pathology is complex and incompletely understood. Besides accumulation of peroxisomal educts (like very-long-chain fatty acids [VLCFAs] or branched-chain fatty acids) and lack of products (like bile acids or plasmalogens), many peroxisomal defects lead to detrimental mitochondrial abnormalities for unknown reasons. We generated Pex19 Drosophila mutants, which recapitulate the hallmarks of PBDs, like absence of peroxisomes, reduced viability, neurodegeneration, mitochondrial abnormalities, and accumulation of VLCFAs. We present a model of hepatocyte nuclear factor 4 (Hnf4)-induced lipotoxicity and accumulation of free fatty acids as the cause for mitochondrial damage in consequence of peroxisome loss in Pex19 mutants. Hyperactive Hnf4 signaling leads to up-regulation of lipase 3 and enzymes for mitochondrial β-oxidation. This results in enhanced lipolysis, elevated concentrations of free fatty acids, maximal β-oxidation, and mitochondrial abnormalities. Increased acid lipase expression and accumulation of free fatty acids are also present in a Pex19-deficient patient skin fibroblast line, suggesting the conservation of key aspects of our findings.
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Dodt, G., and S. J. Gould. "Multiple PEX genes are required for proper subcellular distribution and stability of Pex5p, the PTS1 receptor: evidence that PTS1 protein import is mediated by a cycling receptor." Journal of Cell Biology 135, no. 6 (December 15, 1996): 1763–74. http://dx.doi.org/10.1083/jcb.135.6.1763.
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PEX5 encodes the type-1 peroxisomal targeting signal (PTS1) receptor, one of at least 15 peroxins required for peroxisome biogenesis. Pex5p has a bimodal distribution within the cell, mostly cytosolic with a small amount bound to peroxisomes. This distribution indicates that Pex5p may function as a cycling receptor, a mode of action likely to require interaction with additional peroxins. Loss of peroxins required for protein translocation into the peroxisome (PEX2 or PEX12) resulted in accumulation of Pex5p at docking sites on the peroxisome surface. Pex5p also accumulated on peroxisomes in normal cells under conditions which inhibit protein translocation into peroxisomes (low temperature or ATP depletion), returned to the cytoplasm when translocation was restored, and reaccumulated on peroxisomes when translocation was again inhibited. Translocation inhibiting conditions did not result in Pex5p redistribution in cells that lack detectable peroxisomes. Thus, it appears that Pex5p can cycle repeatedly between the cytoplasm and peroxisome. Altered activity of the peroxin defective in CG7 cells leads to accumulation of Pex5p within the peroxisome, indicating that Pex5p may actually enter the peroxisome lumen at one point in its cycle. In addition, we found that the PTS1 receptor was extremely unstable in the peroxin-deficient CG1, CG4, and CG8 cells. Altered distribution or stability of the PTS1 receptor in all cells with a defect in PTS1 protein import implies that the genes mutated in these cell lines encode proteins with a direct role in peroxisomal protein import.
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Hugouvieux-Cotte-Pattat, Nicole, Vladimir E. Shevchik, and William Nasser. "PehN, a Polygalacturonase Homologue with a Low Hydrolase Activity, Is Coregulated with the Other Erwinia chrysanthemi Polygalacturonases." Journal of Bacteriology 184, no. 10 (May 15, 2002): 2664–73. http://dx.doi.org/10.1128/jb.184.10.2664-2673.2002.
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ABSTRACT Erwinia chrysanthemi 3937 secretes an arsenal of pectinolytic enzymes, including at least eight endo-pectate lyases encoded by pel genes, which play a major role in the soft-rot disease caused by this bacterium on various plants. E. chrysanthemi also produces some hydrolases that cleave pectin. Three adjacent hydrolase genes, pehV, pehW, and pehX, encoding exo-poly-α-d-galacturonosidases, have been characterized. These enzymes liberate digalacturonides from the nonreducing end of pectin. We report the identification of a novel gene, named pehN, encoding a protein homologous to the glycosyl hydrolases of family 28, which includes mainly polygalacturonases. PehN has a low hydrolase activity on polygalacturonate and on various pectins. PehN action favors the activity of the secreted endo-pectate lyases, mainly PelB and PelC, and that of the periplasmic exo-pectate lyase PelX. However, removal of the pehN gene does not significantly alter the virulence of E. chrysanthemi. Regulation of pehN transcription was analyzed by using gene fusions. Like other pectinase genes, pehN transcription is dependent on several environmental conditions. It is induced by pectic catabolic products and is affected by growth phase, catabolite repression, osmolarity, anaerobiosis, nitrogen starvation, and the presence of calcium ions. The transcription of pehN is modulated by the repressor KdgR, which controls almost all the steps of pectin catabolism, and by cyclic AMP receptor protein (CRP), the global activator of sugar catabolism. The regulator PecS, which represses the transcription of the pel genes but activates that of pehV, pehW, and pehX, also activates transcription of pehN. The three regulators KdgR, PecS, and CRP act by direct interaction with the pehN promoter region. The sequences involved in the binding of these three regulators and of RNA polymerase have been precisely defined. Analysis of the simultaneous binding of these proteins indicates that CRP and RNA polymerase bind cooperatively and that the binding of KdgR could prevent pehN transcription. In contrast, the activator effect of PecS is not linked to competition with KdgR or to cooperation with CRP or RNA polymerase. This effect probably results from competition between PecS and an unidentified repressor involved in peh regulation.
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Ferreira Alves, César Augusto Pinheiro, Luisa Norbert Simonsen, Jonathan Rodrigues, Isabella Peixoto de Barcelos, Clarissa Bueno, Ramon Moura Dos Santos, Fernando Kok, and Leandro Tavares Lucato. "PEX6: An Imaging Overlap Between Peroxisomal and Lysosomal Storage Diseases." Journal of Human and Clinical Genetics 2, no. 2 (October 1, 2020): 28–32. http://dx.doi.org/10.29245/2690-0009/2020/2.1116.
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Peroxisomal disorders are a group of expanding genetic diseases divided into two major categories: peroxisome biogenesis defects (Zellweger spectrum disorder), and single enzymatic defects. Disorders of Peroxisome Biogenesis occur when there are biallelic pathogenic variants in any of the 13 PEX genes, which code for the peroxins, proteins required for peroxisome biogenesis. This group of disorders includes two distinct phenotypes: Rhizomelic Chondrodysplasia Punctata Type-1 and Zellweger Spectrum Disorders (ZSD), of which Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate, and infantile Refsum is the mildest. The spectrum’s most frequent defects are observed in the proteins PEX1 and PEX6, and the most common clinical presentation is Zellweger spectrum, which is often associated with craniofacial dysmorphism with neurologic abnormalities. Typically, the neuroimaging pattern shows several malformative features, including a range of cortical gyral abnormalities such as microgyria and pachygyria, and impairment of the myelination. Nevertheless, we report two siblings with peroxisomal disorder, with unexpected leukodystrophy pattern of the brain mimicking lysosomal storage disease, with classical imaging features of Krabbe disease on brain magnetic resonance image. By whole exome sequencing, we identified two pathogenic variants in compound heterozygosity in PEX6: Chr6:42.933.455 C>T (c.2435G>A), and Chr6:42.935.188 C>T (c.1802G>A). Thus, a final diagnosis of peroxisome disorder was confirmed. The index cases highlight the importance of considering peroxisome disorders as a differential diagnosis for patients with imaging features that resemble Krabbe disease.
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Collins, Cynthia S., Jennifer E. Kalish, James C. Morrell, J. Michael McCaffery, and Stephen J. Gould. "The Peroxisome Biogenesis Factors Pex4p, Pex22p, Pex1p, and Pex6p Act in the Terminal Steps of Peroxisomal Matrix Protein Import." Molecular and Cellular Biology 20, no. 20 (October 15, 2000): 7516–26. http://dx.doi.org/10.1128/mcb.20.20.7516-7526.2000.
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ABSTRACT Peroxisomes are independent organelles found in virtually all eukaryotic cells. Genetic studies have identified more than 20PEX genes that are required for peroxisome biogenesis. The role of most PEX gene products, peroxins, remains to be determined, but a variety of studies have established that Pex5p binds the type 1 peroxisomal targeting signal and is the import receptor for most newly synthesized peroxisomal matrix proteins. The steady-state abundance of Pex5p is unaffected in mostpex mutants of the yeast Pichia pastorisbut is severely reduced in pex4 andpex22 mutants and moderately reduced in pex1and pex6 mutants. We used these subphenotypes to determine the epistatic relationships among several groups ofpex mutants. Our results demonstrate that Pex4p acts after the peroxisome membrane synthesis factor Pex3p, the Pex5p docking factors Pex13p and Pex14p, the matrix protein import factors Pex8p, Pex10p, and Pex12p, and two other peroxins, Pex2p and Pex17p. Pex22p and the interacting AAA ATPases Pex1p and Pex6p were also found to act after Pex10p. Furthermore, Pex1p and Pex6p were found to act upstream of Pex4p and Pex22p. These results suggest that Pex1p, Pex4p, Pex6p, and Pex22p act late in peroxisomal matrix protein import, after matrix protein translocation. This hypothesis is supported by the phenotypes of the corresponding mutant strains. As has been shown previously for P. pastoris pex1,pex6, and pex22 mutant cells, we show here thatpex4Δ mutant cells contain peroxisomal membrane protein-containing peroxisomes that import residual amounts of peroxisomal matrix proteins.
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Mauriac, Stephanie A., Thibault Peineau, Aamir Zuberi, Cathleen Lutz, and Gwénaëlle S. G. Géléoc. "Loss of Pex1 in Inner Ear Hair Cells Contributes to Cochlear Synaptopathy and Hearing Loss." Cells 11, no. 24 (December 9, 2022): 3982. http://dx.doi.org/10.3390/cells11243982.
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Peroxisome Biogenesis Disorders (PBD) and Zellweger syndrome spectrum disorders (ZSD) are rare genetic multisystem disorders that include hearing impairment and are associated with defects in peroxisome assembly, function, or both. Mutations in 13 peroxin (PEX) genes have been found to cause PBD-ZSD with ~70% of patients harboring mutations in PEX1. Limited research has focused on the impact of peroxisomal disorders on auditory function. As sensory hair cells are particularly vulnerable to metabolic changes, we hypothesize that mutations in PEX1 lead to oxidative stress affecting hair cells of the inner ear, subsequently resulting in hair cell degeneration and hearing loss. Global deletion of the Pex1 gene is neonatal lethal in mice, impairing any postnatal studies. To overcome this limitation, we created conditional knockout mice (cKO) using Gfi1Creor VGlut3Cre expressing mice crossed to floxed Pex1 mice to allow for selective deletion of Pex1 in the hair cells of the inner ear. We find that Pex1 excision in inner hair cells (IHCs) leads to progressive hearing loss associated with significant decrease in auditory brainstem responses (ABR), specifically ABR wave I amplitude, indicative of synaptic defects. Analysis of IHC synapses in cKO mice reveals a decrease in ribbon synapse volume and functional alterations in exocytosis. Concomitantly, we observe a decrease in peroxisomal number, indicative of oxidative stress imbalance. Taken together, these results suggest a critical function of Pex1 in development and maturation of IHC-spiral ganglion synapses and auditory function.
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Mbekeani, Alison, Will Stanley, Vishal Kalel, Noa Dahan, Einat Zalckvar, Lilach Sheiner, Wolfgang Schliebs, Ralf Erdmann, Ehmke Pohl, and Paul Denny. "Functional Analyses of a Putative, Membrane-Bound, Peroxisomal Protein Import Mechanism from the Apicomplexan Protozoan Toxoplasma gondii." Genes 9, no. 9 (August 29, 2018): 434. http://dx.doi.org/10.3390/genes9090434.
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Peroxisomes are central to eukaryotic metabolism, including the oxidation of fatty acids—which subsequently provide an important source of metabolic energy—and in the biosynthesis of cholesterol and plasmalogens. However, the presence and nature of peroxisomes in the parasitic apicomplexan protozoa remains controversial. A survey of the available genomes revealed that genes encoding peroxisome biogenesis factors, so-called peroxins (Pex), are only present in a subset of these parasites, the coccidia. The basic principle of peroxisomal protein import is evolutionarily conserved, proteins harbouring a peroxisomal-targeting signal 1 (PTS1) interact in the cytosol with the shuttling receptor Pex5 and are then imported into the peroxisome via the membrane-bound protein complex formed by Pex13 and Pex14. Surprisingly, whilst Pex5 is clearly identifiable, Pex13 and, perhaps, Pex14 are apparently absent from the coccidian genomes. To investigate the functionality of the PTS1 import mechanism in these parasites, expression of Pex5 from the model coccidian Toxoplasma gondii was shown to rescue the import defect of Pex5-deleted Saccharomyces cerevisiae. In support of these data, green fluorescent protein (GFP) bearing the enhanced (e)PTS1 known to efficiently localise to peroxisomes in yeast, localised to peroxisome-like bodies when expressed in Toxoplasma. Furthermore, the PTS1-binding domain of Pex5 and a PTS1 ligand from the putatively peroxisome-localised Toxoplasma sterol carrier protein (SCP2) were shown to interact in vitro. Taken together, these data demonstrate that the Pex5–PTS1 interaction is functional in the coccidia and indicate that a nonconventional peroxisomal import mechanism may operate in the absence of Pex13 and Pex14.
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Lambkin, Gareth R., and Richard A. Rachubinski. "Yarrowia lipolyticaCells Mutant for the Peroxisomal Peroxin Pex19p Contain Structures Resembling Wild-Type Peroxisomes." Molecular Biology of the Cell 12, no. 11 (November 2001): 3353–64. http://dx.doi.org/10.1091/mbc.12.11.3353.
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PEX genes encode peroxins, which are proteins required for peroxisome assembly. The PEX19 gene of the yeast Yarrowia lipolytica was isolated by functional complementation of the oleic acid-nonutilizing strainpex19-1 and encodes Pex19p, a protein of 324 amino acids (34,822 Da). Subcellular fractionation and immunofluorescence microscopy showed Pex19p to be localized primarily to peroxisomes. Pex19p is detected in cells grown in glucose-containing medium, and its levels are not increased by incubation of cells in oleic acid–containing medium, the metabolism of which requires intact peroxisomes. pex19 cells preferentially mislocalize peroxisomal matrix proteins and the peripheral intraperoxisomal membrane peroxin Pex16p to the cytosol, although small amounts of these proteins could be reproducibly localized to a subcellular fraction enriched for peroxisomes. In contrast, the peroxisomal integral membrane protein Pex2p exhibits greatly reduced levels inpex19 cells compared with its levels in wild-type cells. Importantly, pex19 cells were shown by electron microscopy to contain structures that resemble wild-type peroxisomes in regards to size, shape, number, and electron density. Subcellular fractionation and isopycnic density gradient centrifugation confirmed the presence of vesicular structures in pex19 mutant strains that were similar in density to wild-type peroxisomes and that contained profiles of peroxisomal matrix and membrane proteins that are similar to, yet distinct from, those of wild-type peroxisomes. Because peroxisomal structures form in pex19 cells, Pex19p apparently does not function as a peroxisomal membrane protein receptor in Y. lipolytica. Our results are consistent with a role for Y. lipolytica Pex19p in stabilizing the peroxisomal membrane.
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ROTTENSTEINER, Hanspeter, Luigi PALMIERI, Andreas HARTIG, Barbara HAMILTON, Helmut RUIS, Ralf ERDMANN, and Aner GURVITZ. "The peroxisomal transporter gene ANT1 is regulated by a deviant oleate response element (ORE): characterization of the signal for fatty acid induction." Biochemical Journal 365, no. 1 (July 1, 2002): 109–17. http://dx.doi.org/10.1042/bj20011495.
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Saccharomyces cerevisiae ANT1/YPR128c encodes the peroxisomal adenine nucleotide transporter that provides ATP for intra-peroxisomal activation of medium-chain fatty acids. A lacZ reporter construct comprising the ANT1 promoter was shown to be comparatively more highly expressed in a wild-type strain grown on oleic acid, a long-chain fatty acid, than in pip2Δoaf1Δ mutant cells that are defective in fatty acid induction. The ANT1 promoter was demonstrated to contain a deviant oleate response element (ORE) that could bind the Pip2p-Oaf1p transcription factor and confer activation on a basal CYC1-lacZ reporter gene. Expression of Ant1p as well as other enzymes whose genes are known to be regulated by a canonical ORE was found to be increased in cells grown on lauric acid, a medium-chain fatty acid. We concluded that the signal for induction does not differentiate between long- and medium-chain fatty acids. This signal was independent of β-oxidation or the biogenesis of the peroxisomal compartment where this process occurs, since a pox1Δ strain blocked in the first and rate-limiting step of β-oxidation as well as various pex mutant cells devoid of intact peroxisomes produced sufficient amounts of Pip2p-Oaf1p for binding OREs in vitro and for expressing an ORE-driven reporter gene. The signal's durability was shown to be related to the concentration of fatty acids in the medium, since a pex6Δ strain expressed an ORE-driven reporter gene at high levels for a longer period than did isogenic wild-type cells. Generation of the signal was also independent of protein synthesis, as demonstrated by cycloheximide treatment.
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Xiao Zhu, Yuan, Laura Bruins, Chang-Xin Shi, Jessica Schmidt, Chris Sereduk, Mia Champion, Esteban Braggio, Holly Yin, and A. Keith Stewart. "A Synthetic Lethality Druggable Genome RNAi Screen Identifies Genes Mediating Sensitivity To Lenalidomide In Multiple Myeloma Including RSK2." Blood 122, no. 21 (November 15, 2013): 3084. http://dx.doi.org/10.1182/blood.v122.21.3084.3084.
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Abstract Immunomodulatory drugs (IMiDs) are widely used in the treatment of patients with Multiple Myeloma (MM) however, only 30% of relapsed MM patients respond to single agent therapy and most patients eventually develop drug resistance. The molecular target of IMiDs in MM is cereblon but other parallel pathways or downstream events which enhance or preclude drug responsiveness are unknown. We therefore conducted a genome scale small interfering RNA (siRNA) lethality study in MM in the presence of increasing concentrations of lenalidomide. Primary screening was performed in a single-siRNA-per-well format with the human druggable genome siRNA set V4 comprising four siRNAs targeting each of 6,992 genes (total 27968 siRNAs). Lenalidomide was added 24 hours post transfection and cell viability was measured by ATP-dependent luminescence at 144 hours after transfection. Primary screen data was rigorously evaluated for multiple quality control metrics and found to exceed all expected performance parameters with >98% global transfection efficiency, <0.25 CV values, and minimal plate-to-plate and set-to-set variations observed. Hit selection was performed by analysis of IC50 value shift in the presence of each testing siRNA compared with three different control siRNA oligos. 160 candidate genes that enhance lenalidomide sensitivity upon silencing (sensitizers) were selected and re-screened with four siRNA oligos targeting each gene. 50 genes were identified as reproducible lenalidomide sensitizers including three Peroxisome (PEX) family proteins (PEX1, PEX10 and PEX7) and seven RAB family proteins (RAB17, RAB1A, RAB26, RAB30, RAB36, RAB4A and RAB8A). Four kinase genes were also identified in sensitizer hits and two of these, I-Kappa-B Kinase-Alpha (IKK1 or CHUK) and ribosomal protein S6 kinase (RPS6KA3 or RSK2), encode proteins that associate with significance together with a phosphorylation dependent transcription factor (CREB1) in Toll signaling pathways (p-value 0.0068). RSK2 is a serine/threonine-protein kinase that acts downstream of oncogenic FGFR3 mediated signaling and is phosphorylated by ERK (MAPK1/ERK2 and MAPK3/ERK1 signaling) during hematopoietic transformation. Phosphorylated RSK2 was previously reported to be frequently expressed in myeloma cell lines and primary myeloma cells. Using lentiviral shRNA expression, we demonstrated that knockdown of RSK2 in three genetically variable MM cell lines induced cyctocytoxiticy and consistently sensitized to lenalidomide. Two selective small molecular inhibitors of RSK2 (SL 0101-1 and BI-D1870) were then demonstrated to synergize with lenalidomide to induce myeloma cell cytotoxicixity. To further understand the mechanism underlying sensitization, immunoblotting analysis was performed to look at downstream changes after either RSK2 knockdown or RSK2 inhibition by BI-D1870. We found that both RSK2 knockdown and BI-D1870 treatment, mimicking lenalidomide treatment or cereblon inhibition, induced downregulation of both IRF4 and MYC in MM cells. The combination of lenalidomide and BI-D1870 not only produced a substantial synergistic effect inducing MM cytotoxicity, but also demonstrated a significant enhancement of downregulation of IRF4 and MYC. Forced overexpression of RSK2 attenuated the synergistic effects of lenalidomide and BI-D1870. In summary, our high throughput screen identified multiple gene targets that associate with increasing sensitivity to IMiDs in MM cells, of which, RSK2 was further validated by both shRNA silencing and specific inhibitors as an effective target to cooperate with IMiDs to induce myeloma cytotoxicity. Clinical studies of RSK2 inhibition in concert with IMiD (cereblon inhibitor) therapy would be appropriate. Disclosures: Stewart: Onyx: Consultancy, Research Funding; Millennium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria.
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Asahara, Hiroshi, Sanjoy Dutta, Hung-Ying Kao, Ronald M. Evans, and Marc Montminy. "Pbx-Hox Heterodimers Recruit Coactivator-Corepressor Complexes in an Isoform-Specific Manner." Molecular and Cellular Biology 19, no. 12 (December 1, 1999): 8219–25. http://dx.doi.org/10.1128/mcb.19.12.8219.
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ABSTRACT Homeobox (hox) proteins have been shown to regulate cell fate and segment identity by promoting the expression of specific genetic programs. In contrast to their restricted biological action in vivo, however, most homeodomain factors exhibit promiscuous DNA binding properties in vitro, suggesting a requirement for additional cofactors that enhance target site selectivity. In this regard, thepbx family of homeobox genes has been found to heterodimerize with and thereby augment the DNA binding activity of certain hox proteins on a subset of potential target sites. Here we examine the transcriptional properties of a forcedhox-pbx heterodimer containing the pancreas-specific orphan homeobox factor pdx fused to pbx-1a. Compared to the pdx monomer, the forced pdx-pbx1a dimer, displayed 10- to 20-fold-higher affinity for a consensushox-pbx binding site but was completely unable to bind ahox monomer recognition site. The pdx-pbx dimer stimulated target gene expression via an N-terminaltrans-activation domain in pdx that interacts with the coactivator CREB binding protein. The pdx-pbxdimer was also found to repress transcription via a C-terminal domain in pbx-1a that associates with the corepressors SMRT and NCoR. The transcriptional properties of the pdx-pbx1complex appear to be regulated at the level of alternative splicing; apdx-pbx polypeptide containing the pbx1bisoform, which lacks the C-terminal extension in pbx1a, was unable to repress target gene expression via NCoR-SMRT. Sincepbx1a and pbx1b are differentially expressed in endocrine versus exocrine compartments of the adult pancreas, our results illustrate a novel mechanism by which pbx proteins may modulate the expression of specific genetic programs, either positively or negatively, during development.
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Strachan, Tom, and Andrew P. Read. "PAX genes." Current Opinion in Genetics & Development 4, no. 3 (June 1994): 427–38. http://dx.doi.org/10.1016/0959-437x(94)90032-9.
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Liu, Yang, Guoqiao Jiang, Yaya Cui, Asita Mukherjee, Wei Lei Ma, and Arun K. Chatterjee. "kdgREcc Negatively Regulates Genes for Pectinases, Cellulase, Protease, HarpinEcc, and a Global RNA Regulator in Erwinia carotovora subsp.carotovora." Journal of Bacteriology 181, no. 8 (April 15, 1999): 2411–21. http://dx.doi.org/10.1128/jb.181.8.2411-2421.1999.
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ABSTRACT Erwinia carotovora subsp. carotovoraproduces extracellular pectate lyase (Pel), polygalacturonase (Peh), cellulase (Cel), and protease (Prt). The concerted actions of these enzymes largely determine the virulence of this plant-pathogenic bacterium. E. carotovora subsp. carotovoraalso produces HarpinEcc, the elicitor of the hypersensitive reaction. We document here that KdgREcc (Kdg, 2-keto-3-deoxygluconate; KdgR, general repressor of genes involved in pectin and galacturonate catabolism), a homolog of the E. chrysanthemi repressor, KdgREch and theEscherichia coli repressor, KdgREco, negatively controls not only the pectinases, Pel and Peh, but also Cel, Prt, and HarpinEcc production in E. carotovorasubsp. carotovora. The levels of pel-1,peh-1, celV, andhrpNEcc transcripts are markedly affected by KdgREcc. The KdgREcc − mutant is more virulent than the KdgREcc + parent. Thus, our data for the first time establish a global regulatory role for KdgREcc in E. carotovora subsp.carotovora. Another novel observation is the negative effect of KdgREcc on the transcription of rsmB(previously aepH), which specifies an RNA regulator controlling exoenzyme and HarpinEcc production. The levels of rsmB RNA are higher in the KdgREcc − mutant than in the KdgREcc + parent. Moreover, by DNase I protection assays we determined that purified KdgREccprotected three 25-bp regions within the transcriptional unit ofrsmB. Alignment of the protected sequences revealed the 21-mer consensus sequence of the KdgREcc-binding site as 5′-G/AA/TA/TGAAA[N6]TTTCAG/TG/TA-3′. Two such KdgREcc-binding sites occur inrsmB DNA in a close proximity to each other within nucleotides +79 and +139 and the third KdgREcc-binding site within nucleotides +207 and +231. Analysis of lacZtranscriptional fusions shows that the KdgR-binding sites negatively affect the expression of rsmB. KdgREcc also binds the operator DNAs of pel-1 and peh-1genes and represses expression of a pel1-lacZ and apeh1-lacZ transcriptional fusions. We conclude that KdgREcc affects extracellular enzyme production by two ways: (i) directly, by inhibiting the transcription of exoenzyme genes; and (ii) indirectly, by preventing the production of a global RNA regulator. Our findings support the idea that KdgREccaffects transcription by promoter occlusion, i.e., preventing the initiation of transcription, and by a roadblock mechanism, i.e., by affecting the elongation of transcription.
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Stuart, E. T., C. Kioussi, and P. Gruss. "Mammalian Pax Genes." Annual Review of Genetics 28, no. 1 (December 1994): 219–38. http://dx.doi.org/10.1146/annurev.ge.28.120194.001251.
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Matsumoto, Hiroyuki, Pongphen Jitareerat, Yasuhiro Baba, and Shinji Tsuyumu. "Comparative Study of Regulatory Mechanisms for Pectinase Production by Erwinia carotovora subsp. carotovora and Erwinia chrysanthemi." Molecular Plant-Microbe Interactions® 16, no. 3 (March 2003): 226–37. http://dx.doi.org/10.1094/mpmi.2003.16.3.226.
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The production of pectinase, the major virulence determinant of soft-rot Erwinia species, is controlled by many regulatory factors. We focused on the major regulatory proteins, KdgR, CRP, Pir, and PecS, characterized mainly in E. chrysanthemi, and tested for their presence and function in the control of pectate lyase (Pel) and polygalacturonase (Peh) production in E. carotovora subsp. carotovora. Homologues of kdgR and crp but not of pir and pecS were detected by Southern blot analyses in E. carotovora subsp. carotovora. In fact, KdgR and CRP homologues of E. carotovora subsp. carotovora had high amino acid identities to those of E. chrysanthemi, including a complete match of the hypothetical helix-turn-helix DNA-binding motif. However, in Western blot analyses using anti-Pir (E. chrysanthemi) antibodies, a cross-reacting protein was present in both Erwinia species, although Pel production in E. carotovora subsp. carotovora was not further stimulated by adding plant extract into the medium containing PGA (polygalac-turonic acid) in which hyperinduction by Pir has been reported in E. chrysanthemi EC16. When plasmids that contained each of these regulatory genes from E. chrysanthemi were introduced into E. carotovora subsp. carotovora, Pel production was controlled as predicted from their roles in E. chrysanthemi, except for PecS. PecS exerted a positive control in E. carotovora subsp. carotovora, in contrast to a negative control in E. chrysanthemi. DNA-binding assays demonstrated that KdgR, CRP, Pir, and PecS of E. chrysanthemi and KdgR and CRP homologues of E. carotovora subsp. carotovora could bind to the promoter regions of pel-1, pel-3, and peh of E. carotovora subsp. carotovora. Taken together, KdgR and CRP homologues of E. carotovora subsp. carotovora may regulate Pel and Peh production as in E. chrysanthemi. However, the presence of Pir and PecS homologues in E. carotovora subsp. carotovora was not identified in this study, though these proteins of E. chrysanthemi were functional on the promoter regions of the pectinase genes of E. carotovora subsp. carotovora.
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Mansouri, A., A. Stoykova, and P. Gruss. "Pax genes in development." Journal of Cell Science 1994, Supplement 18 (January 1, 1994): 35–42. http://dx.doi.org/10.1242/jcs.1994.supplement_18.5.
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Dahl, Edgar, Haruhiko Koseki, and Rudi Balling. "Pax genes and organogenesis." BioEssays 19, no. 9 (September 1997): 755–65. http://dx.doi.org/10.1002/bies.950190905.
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Shevchik, Vladimir E., Harry C. M. Kester, Jacques A. E. Benen, Jaap Visser, Janine Robert-Baudouy, and Nicole Hugouvieux-Cotte-Pattat. "Characterization of the Exopolygalacturonate Lyase PelX of Erwinia chrysanthemi 3937." Journal of Bacteriology 181, no. 5 (March 1, 1999): 1652–63. http://dx.doi.org/10.1128/jb.181.5.1652-1663.1999.
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ABSTRACT Erwinia chrysanthemi 3937 secretes several pectinolytic enzymes, among which eight isoenzymes of pectate lyases with an endo-cleaving mode (PelA, PelB, PelC, PelD, PelE, PelI, PelL, and PelZ) have been identified. Two exo-cleaving enzymes, the exopolygalacturonate lyase, PelX, and an exo-poly-α-d-galacturonosidase, PehX, have been previously identified in other E. chrysanthemi strains. Using a genomic bank of a 3937 mutant with the major pelgenes deleted, we cloned a pectinase gene identified aspelX, encoding the exopolygalacturonate lyase. The deduced amino acid sequence of the 3937 PelX is very similar to the PelX of another E. chrysanthemi strain, EC16, except in the 43 C-terminal amino acids. PelX also has homology to the endo-pectate lyase PelL of E. chrysanthemi but has a N-terminal extension of 324 residues. The transcription of pelX, analyzed by gene fusions, is dependent on several environmental conditions. It is induced by pectic catabolic products and affected by growth phase, oxygen limitation, nitrogen starvation, and catabolite repression. Regulation of pelX expression is dependent on the KdgR repressor, which controls almost all the steps of pectin catabolism, and on the global activator of sugar catabolism, cyclic AMP receptor protein. In contrast, PecS and PecT, two repressors of the transcription of most pectate lyase genes, are not involved inpelX expression. The pelX mutant displayed reduced pathogenicity on chicory leaves, but its virulence on potato tubers or Saintpaulia ionantha plants did not appear to be affected. The purified PelX protein has no maceration activity on plant tissues. Tetragalacturonate is the best substrate of PelX, but PelX also has good activity on longer oligomers. Therefore, the estimated number of binding subsites for PelX is 4, extending from subsites −2 to +2. PelX and PehX were shown to be localized in the periplasm ofE. chrysanthemi 3937. PelX catalyzed the formation of unsaturated digalacturonates by attack from the reducing end of the substrate, while PehX released digalacturonates by attack from the nonreducing end of the substrate. Thus, the two types of exo-degrading enzymes appeared complementary in the degradation of pectic polymers, since they act on both extremities of the polymeric chain.
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Temporini, Esteban, and Hans VanEtten. "Distribution of the pea pathogenicity ( PEP ) genes in the fungus Nectria haematococca mating population VI." Current Genetics 41, no. 2 (May 1, 2002): 107–14. http://dx.doi.org/10.1007/s00294-002-0279-x.
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Steele, Rebecca E., Rachel Sanders, Helen M. Phillips, and Simon D. Bamforth. "PAX Genes in Cardiovascular Development." International Journal of Molecular Sciences 23, no. 14 (July 12, 2022): 7713. http://dx.doi.org/10.3390/ijms23147713.
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The mammalian heart is a four-chambered organ with systemic and pulmonary circulations to deliver oxygenated blood to the body, and a tightly regulated genetic network exists to shape normal development of the heart and its associated major arteries. A key process during cardiovascular morphogenesis is the septation of the outflow tract which initially forms as a single vessel before separating into the aorta and pulmonary trunk. The outflow tract connects to the aortic arch arteries which are derived from the pharyngeal arch arteries. Congenital heart defects are a major cause of death and morbidity and are frequently associated with a failure to deliver oxygenated blood to the body. The Pax transcription factor family is characterised through their highly conserved paired box and DNA binding domains and are crucial in organogenesis, regulating the development of a wide range of cells, organs and tissues including the cardiovascular system. Studies altering the expression of these genes in murine models, notably Pax3 and Pax9, have found a range of cardiovascular patterning abnormalities such as interruption of the aortic arch and common arterial trunk. This suggests that these Pax genes play a crucial role in the regulatory networks governing cardiovascular development.