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1.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281263

RESUMO

Cholesterol is a foundational molecule of biology. There is a long-standing interest in understanding how cholesterol metabolism is intertwined with cancer biology. In this review, we focus on the known connections between lung cancer and molecules mediating cholesterol efflux. A major take-home lesson is that the roles of many cholesterol efflux factors remain underexplored. It is our hope that this article would motivate others to investigate how cholesterol efflux factors contribute to lung cancer biology.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol/metabolismo , Neoplasias Pulmonares/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Transporte Biológico Ativo , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos
2.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198763

RESUMO

ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of conserved proteins from bacteria to mammals. In humans, three members of this family are expressed in the peroxisomal membrane and belong to the subfamily D: ABCD1 (ALDP), ABCD2 (ALDRP), and ABCD3 (PMP70). These half-transporters must dimerize to form a functional transporter, but they are thought to exist primarily as tetramers. They possess overlapping but specific substrate specificity, allowing the transport of various lipids into the peroxisomal matrix. The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively. In addition to their role in peroxisome metabolism, it has recently been proposed that peroxisomal ABC transporters participate in cell signaling and cell control, particularly in cancer. This review presents an overview of the knowledge on the structure, function, and mechanisms involving these proteins and their link to pathologies. We summarize the different in vitro and in vivo models existing across the species to study peroxisomal ABC transporters and the consequences of their defects. Finally, an overview of the known and possible interactome involving these proteins, which reveal putative and unexpected new functions, is shown and discussed.


Assuntos
Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Subfamília D de Transportador de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/patologia , Colestase/genética , Colestase/patologia , Ácidos Graxos/genética , Humanos , Peroxissomos/genética
3.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207256

RESUMO

ATP-binding cassette (ABC) transporter proteins are a gene super-family in plants and play vital roles in growth, development, and response to abiotic and biotic stresses. The ABC transporters have been identified in crop plants such as rice and buckwheat, but little is known about them in soybean. Soybean is an important oil crop and is one of the five major crops in the world. In this study, 255 ABC genes that putatively encode ABC transporters were identified from soybean through bioinformatics and then categorized into eight subfamilies, including 7 ABCAs, 52 ABCBs, 48 ABCCs, 5 ABCDs, 1 ABCEs, 10 ABCFs, 111 ABCGs, and 21 ABCIs. Their phylogenetic relationships, gene structure, and gene expression profiles were characterized. Segmental duplication was the main reason for the expansion of the GmABC genes. Ka/Ks analysis suggested that intense purifying selection was accompanied by the evolution of GmABC genes. The genome-wide collinearity of soybean with other species showed that GmABCs were relatively conserved and that collinear ABCs between species may have originated from the same ancestor. Gene expression analysis of GmABCs revealed the distinct expression pattern in different tissues and diverse developmental stages. The candidate genes GmABCB23, GmABCB25, GmABCB48, GmABCB52, GmABCI1, GmABCI5, and GmABCI13 were responsive to Al toxicity. This work on the GmABC gene family provides useful information for future studies on ABC transporters in soybean and potential targets for the cultivation of new germplasm resources of aluminum-tolerant soybean.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Alumínio/toxicidade , Proteínas de Plantas/metabolismo , Soja/genética , Transportadores de Cassetes de Ligação de ATP/genética , Resistência a Medicamentos/genética , Proteínas de Plantas/genética , Soja/efeitos dos fármacos , Soja/metabolismo
4.
BMC Genomics ; 22(1): 553, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281528

RESUMO

BACKGROUND: The ATP-binding cassette (ABC) transporter superfamily is comprised predominantly of proteins which directly utilize energy from ATP to move molecules across the plasma membrane. Although they have been the subject of frequent investigation across many taxa, arthropod ABCs have been less well studied. While the manual annotation of ABC transporters has been performed in many arthropods, there has so far been no systematic comparison of the superfamily within this order using the increasing number of sequenced genomes. Furthermore, functional work on these genes is limited. RESULTS: Here, we developed a standardized pipeline to annotate ABCs from predicted proteomes and used it to perform comparative genomics on ABC families across arthropod lineages. Using Kruskal-Wallis tests and the Computational Analysis of gene Family Evolution (CAFE), we were able to observe significant expansions of the ABC-B full transporters (P-glycoproteins) in Lepidoptera and the ABC-H transporters in Hemiptera. RNA-sequencing of epithelia tissues in the Lepidoptera Helicoverpa armigera showed that the 7 P-glycoprotein paralogues differ substantially in their tissue distribution, suggesting a spatial division of labor. It also seems that functional redundancy is a feature of these transporters as RNAi knockdown showed that most transporters are dispensable with the exception of the highly conserved gene Snu, which is probably due to its role in cuticular formation. CONCLUSIONS: We have performed an annotation of the ABC superfamily across > 150 arthropod species for which good quality protein annotations exist. Our findings highlight specific expansions of ABC transporter families which suggest evolutionary adaptation. Future work will be able to use this analysis as a resource to provide a better understanding of the ABC superfamily in arthropods.


Assuntos
Artrópodes , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Artrópodes/genética , Genoma , Genômica , Humanos , Anotação de Sequência Molecular
5.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072847

RESUMO

Many proteins have a multimeric structure and are composed of two or more identical subunits. While this can be advantageous for the host organism, it can be a challenge when targeting specific residues in biochemical analyses. In vitro splitting and re-dimerization to circumvent this problem is a tedious process that requires stable proteins. We present an in vivo approach to transform homodimeric proteins into apparent heterodimers, which then can be purified using two-step affinity-tag purification. This opens the door to both practical applications such as smFRET to probe the conformational dynamics of homooligomeric proteins and fundamental research into the mechanism of protein multimerization, which is largely unexplored for membrane proteins. We show that expression conditions are key for the formation of heterodimers and that the order of the differential purification and reconstitution of the protein into nanodiscs is important for a functional ABC-transporter complex.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Bacillus subtilis/genética , Proteínas de Bactérias/genética , Lipoproteínas/genética , Complexos Multiproteicos/genética , Transportadores de Cassetes de Ligação de ATP/ultraestrutura , Adenosina Trifosfatases/genética , Sequência de Aminoácidos/genética , Proteínas de Bactérias/ultraestrutura , Dimerização , Transferência Ressonante de Energia de Fluorescência , Lipoproteínas/ultraestrutura , Complexos Multiproteicos/ultraestrutura , Multimerização Proteica/genética , Subunidades Proteicas/genética
6.
Nat Commun ; 12(1): 3577, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117249

RESUMO

Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.


Assuntos
Antibacterianos/farmacologia , Diterpenos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Lincosamidas/farmacologia , Compostos Policíclicos/farmacologia , Estreptograminas/farmacologia , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adesinas Bacterianas/química , Adesinas Bacterianas/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Microscopia Crioeletrônica , Farmacorresistência Bacteriana/genética , Bactérias Gram-Positivas/genética , Modelos Moleculares , Peptidil Transferases/metabolismo , Conformação Proteica , RNA Mensageiro , Ribossomos/metabolismo
7.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065402

RESUMO

Lung carcinoma is still the most common malignancy worldwide. One of the major subtypes of non-small cell lung cancer (NSCLC) is adenocarcinoma (AC). As driver mutations and hence therapies differ in AC subtypes, we theorized that the expression and function of ABC drug transporters important in multidrug resistance (MDR) would correlate with characteristic driver mutations KRAS or EGFR. Cisplatin resistance (CR) was generated in A549 (KRAS) and PC9 (EGFR) cell lines and gene expression was tested. In three-dimensional (3D) multicellular aggregate cultures, both ABCB1 and ABCG2 transporters, as well as the WNT microenvironment, were investigated. ABCB1 and ABCG2 gene expression levels were different in primary AC samples and correlated with specific driver mutations. The drug transporter expression pattern of parental A549 and PC9, as well as A549-CR and PC9-CR, cell lines differed. Increased mRNA levels of ABCB1 and ABCG2 were detected in A549-CR cells, compared to parental A549, while the trend observed in the case of PC9 cells was different. Dominant alterations were observed in LEF1, RHOU and DACT1 genes of the WNT signalling pathway in a mutation-dependent manner. The study confirmed that, in lung AC-s, KRAS and EGFR driver mutations differentially affect both drug transporter expression and the cisplatin-induced WNT signalling microenvironment.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Células A549 , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Cisplatino/farmacologia , Receptores ErbB/genética , Feminino , Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/genética
8.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065855

RESUMO

To identify the physiological factors that limit the growth of Escherichia coli K-12 strains synthesizing minimal lipopolysaccharide (LPS), we describe the first construction of strains devoid of the entire waa locus and concomitantly lacking all three acyltransferases (LpxL/LpxM/LpxP), synthesizing minimal lipid IVA derivatives with a restricted ability to grow at around 21 °C. Suppressors restoring growth up to 37 °C of Δ(gmhD-waaA) identified two independent single-amino-acid substitutions-P50S and R310S-in the LPS flippase MsbA. Interestingly, the cardiolipin synthase-encoding gene clsA was found to be essential for the growth of ΔlpxLMP, ΔlpxL, ΔwaaA, and Δ(gmhD-waaA) bacteria, with a conditional lethal phenotype of Δ(clsA lpxM), which could be overcome by suppressor mutations in MsbA. Suppressor mutations basS A20D or basR G53V, causing a constitutive incorporation of phosphoethanolamine (P-EtN) in the lipid A, could abolish the Ca++ sensitivity of Δ(waaC eptB), thereby compensating for P-EtN absence on the second Kdo. A single-amino-acid OppA S273G substitution is shown to overcome the synthetic lethality of Δ(waaC surA) bacteria, consistent with the chaperone-like function of the OppA oligopeptide-binding protein. Furthermore, overexpression of GcvB sRNA was found to repress the accumulation of LpxC and suppress the lethality of LapAB absence. Thus, this study identifies new and limiting factors in regulating LPS biosynthesis.


Assuntos
Escherichia coli K12/crescimento & desenvolvimento , Genes Essenciais , Lipopolissacarídeos/biossíntese , Lipopolissacarídeos/genética , Transportadores de Cassetes de Ligação de ATP/genética , Aciltransferases/genética , Substituição de Aminoácidos , Proteínas de Bactérias/genética , Cardiolipinas/genética , Escherichia coli K12/genética , Escherichia coli K12/metabolismo , Proteínas de Escherichia coli/genética , Lipoproteínas/genética , Proteínas de Membrana/genética , Mutações Sintéticas Letais , Transferases (Outros Grupos de Fosfato Substituídos)/genética
9.
Aging (Albany NY) ; 13(9): 12896-12918, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952718

RESUMO

Glycolysis ensures energy supply to cancer cells, thereby facilitating tumor progression. Here, we identified glycolysis-related genes that could predict the prognosis of patients with osteosarcoma. We examined 198 glycolysis-related genes that showed differential expression in metastatic and non-metastatic osteosarcoma samples in the TARGET database, and identified three genes (P4HA1, ABCB6, and STC2) for the establishment of a risk signature. Based on the signature, patients in the high-risk group had poor outcomes. An independent Gene Expression Omnibus database GSE21257 was selected as the validation cohort. Receiver operating characteristic curve analysis was performed and the accuracy of predicting the 1- and 3-year survival rates was shown by the areas under the curve. The results were 0.884 and 0.790 in the TARGET database, and 0.740 and 0.759 in the GSE21257, respectively. Furthermore, we applied ESTIMATE algorithm and performed single sample gene set enrichment analysis to compare tumor immunity between high- and low-risk groups. We found that the low-risk group had higher immune scores and immune infiltration levels than the high-risk group. Finally, we chose P4HA1 as a representative gene to verify the function of risk genes in vitro and in vivo and found that P4HA1 could promote the metastasis of osteosarcoma cells. Our study established a novel glycolysis-related risk signature that could predict the prognosis of patients with osteosarcoma.


Assuntos
Biomarcadores Tumorais/genética , Glicólise/genética , Osteossarcoma/mortalidade , Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estimativa de Kaplan-Meier , Masculino , Osteossarcoma/genética , Osteossarcoma/patologia , Pró-Colágeno-Prolina Dioxigenase/genética , Prognóstico , Curva ROC , Medição de Risco/métodos , Fatores de Risco , Taxa de Sobrevida , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
10.
Hum Genet ; 140(8): 1201-1216, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33978893

RESUMO

Intermediate-sized insertions are one of the structural variants contributing to genome diversity. However, due to technical difficulties in identifying them, their importance in disease pathogenicity and gene expression regulation remains unclear. We used whole-genome sequencing data of 174 Japanese samples to characterize intermediate-sized insertions using a highly-accurate insertion calling method (IMSindel software and joint-call recovery) and obtained a catalogue of 4254 insertions. We constructed an imputation panel comprising of insertions and SNVs from all samples, and conducted imputation of intermediate-sized insertions for 82 publicly-available Japanese samples. Positive Predictive Value of imputation, evaluated using Nanopore long-read sequencing data, was 97%. Subsequent eQTL analysis predicted 128 (~ 3.0%) insertions as causative for gene expression level changes. Enrichment analysis of causal insertions for genome regulatory elements showed significant associations with CTCF-binding sites, super-enhancers, and promoters. Among 17 causal insertions found in the same causal set with GWAS hits, there were insertions associated with changes in expression of cancer-related genes such as BRCA1, ZNF222, and ABCB10. Analysis of insertions sequences revealed that 461 insertions were short tandem duplications frequently found in early-replicating regions of genome. Furthermore, comparison of functional importance of intermediate-sized insertions with that of intermediate-sized deletions detected in the same sample set in our previous study showed that insertions were more frequent in genic regions, and proportion of functional candidates was smaller in insertions. Here, we characterize a high-confidence set of intermediate-sized insertions and indicate their importance in gene expression regulation. Our results emphasize the importance of considering intermediate-sized insertions in trait association studies.


Assuntos
Regulação da Expressão Gênica , Genoma Humano , Mutagênese Insercional , Proteínas de Neoplasias/genética , Neoplasias/genética , Osteoartrite/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Sequência de Bases , Sítios de Ligação , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Mapeamento Cromossômico , Bases de Dados Genéticas , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Humanos , Japão , Anotação de Sequência Molecular , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Software , Sequenciamento Completo do Genoma
11.
BMC Genomics ; 22(1): 315, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933003

RESUMO

BACKGROUND: ATP-binding cassette (ABC) transporters have been found to play important roles in metabolic transport in plant cells, influencing subcellular compartmentalisation and tissue distribution of these metabolic compounds. Salvia miltiorrhiza Bunge, known as Danshen in traditional Chinese medicine, is a highly valued medicinal plant used to treat cardiovascular and cerebrovascular diseases. The dry roots and rhizomes of S. miltiorrhiza contain biologically active secondary metabolites of tanshinone and salvianolic acid. Given an assembled and annotated genome and a set of transcriptome data of S. miltiorrhiza, we analysed and identified the candidate genes that likely involved in the bioactive metabolite transportation of this medicinal plant, starting with the members of the ABC transporter family. RESULTS: A total of 114 genes encoding ABC transporters were identified in the genome of S. miltiorrhiza. All of these ABC genes were divided into eight subfamilies: 3ABCA, 31ABCB, 14ABCC, 2ABCD, 1ABCE, 7ABCF, 46ABCG, and 10 ABCI. Gene expression analysis revealed tissue-specific expression profiles of these ABC transporters. In particular, we found 18 highly expressed transporters in the roots of S. miltiorrhiza, which might be involved in transporting the bioactive compounds of this medicinal plant. We further investigated the co-expression profiling of these 18 genes with key enzyme genes involved in tanshinone and salvianolic acid biosynthetic pathways using quantitative reverse transcription polymerase chain reaction (RT-qPCR). From this RT-qPCR validation, we found that three ABC genes (SmABCG46, SmABCG40, and SmABCG4) and another gene (SmABCC1) co-expressed with the key biosynthetic enzymes of these two compounds, respectively, and thus might be involved in tanshinone and salvianolic acid transport in root cells. In addition, we predicted the biological functions of S. miltiorrhiza ABC transporters using phylogenetic relationships and analysis of the transcriptome to find biological functions. CONCLUSIONS: Here, we present the first systematic analysis of ABC transporters in S. miltiorrhiza and predict candidate transporters involved in bioactive compound transportation in this important medicinal plant. Using genome-wide identification, transcriptome profile analysis, and phylogenetic relationships, this research provides a new perspective on the critical functions of ABC transporters in S. miltiorrhiza.


Assuntos
Salvia miltiorrhiza , Transportadores de Cassetes de Ligação de ATP/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Filogenia , Raízes de Plantas/genética , Salvia miltiorrhiza/genética
12.
Biomed Khim ; 67(2): 137-143, 2021 Mar.
Artigo em Russo | MEDLINE | ID: mdl-33860770

RESUMO

DyeCycle Violet efflux, caused by ATP-binding cassette transporters activity, was analyzed in human colorectal adenocarcinoma cell lines SW480, HT-29, Caco-2 by neans of FACSAria III flow cytometer and ImageStreamX Mk II imaging flow cytometer. Along with similarity of cytometry data obtained on the two instruments, the use of imaging flow cytometry made it possible to characterize the morphology of side population cells, as well as morphology of other cell populations differing in the degree of dye accumulation. The population of cells, which are smaller than the side population cells and practically do not take the dye, is of the special interest. Probably, this population may contribute to the tumor resistance to chemotherapy.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Corantes Fluorescentes , Transportadores de Cassetes de Ligação de ATP/genética , Benzimidazóis , Células CACO-2 , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos
13.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924840

RESUMO

The discovery of novel intronic variants in the ABCA4 locus has contributed significantly to solving the missing heritability in Stargardt disease (STGD1). The increasing number of variants affecting pre-mRNA splicing makes ABCA4 a suitable candidate for antisense oligonucleotide (AON)-based splicing modulation therapies. In this study, AON-based splicing modulation was assessed for 15 recently described intronic variants (three near-exon and 12 deep-intronic variants). In total, 26 AONs were designed and tested in vitro using a midigene-based splice system. Overall, partial or complete splicing correction was observed for two variants causing exon elongation and all variants causing pseudoexon inclusion. Together, our results confirm the high potential of AONs for the development of future RNA therapies to correct splicing defects causing STGD1.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Oligonucleotídeos Antissenso/uso terapêutico , Splicing de RNA/efeitos dos fármacos , Doença de Stargardt/genética , Humanos , Íntrons , Oligonucleotídeos Antissenso/farmacologia , Doença de Stargardt/tratamento farmacológico
14.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925691

RESUMO

Several studies, including genome wide association studies (GWAS), have strongly suggested a central role for the ATP-binding cassette transporter subfamily A member 7 (ABCA7) in Alzheimer's disease (AD). This ABC transporter is now considered as an important genetic determinant for late onset Alzheimer disease (LOAD) by regulating several molecular processes such as cholesterol metabolism and amyloid processing and clearance. In this review we shed light on these new functions and their cross-talk, explaining its implication in brain functioning, and therefore in AD onset and development.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Colesterol/metabolismo , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Fagocitose/fisiologia , Polimorfismo de Nucleotídeo Único/genética
15.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925341

RESUMO

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the "PXE gene" and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.


Assuntos
Calcificação Fisiológica/genética , Calcificação Fisiológica/fisiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , 5'-Nucleotidase/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Calcinose , Difosfatos/metabolismo , Proteínas Ligadas por GPI/genética , Humanos , Artropatias , Camundongos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Pseudoxantoma Elástico/genética , Pseudoxantoma Elástico/fisiopatologia , Pirofosfatases/genética , Pirofosfatases/metabolismo , Ratos , Calcificação Vascular , Doenças Vasculares
16.
Gene ; 788: 145637, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33848571

RESUMO

The pleiotropic drug resistance (PDR) proteins of the ATP-binding cassette (ABC) family play essential roles in physiological processes and have been characterized in many plant species. However, no comprehensive investigation of tobacco (Nicotiana tabacum), an important economic crop and a useful model plant for scientific research, has been presented. We identified 32 PDR genes in the tobacco genome and explored their domain organization, chromosomal distribution and evolution, promoter cis-elements, and expression profiles. A phylogenetic analysis revealed that tobacco has a significantly expanded number of PDR genes involved in plant defense. It also revealed that two tobacco PDR proteins may function as strigolactone transporters to regulate shoot branching, and several NtPDR genes may be involved in cadmium transport. Moreover, tissue expression profiles of NtPDR genes and their responses to several hormones and abiotic stresses were assessed using quantitative real-time PCR. Most of the NtPDR genes were regulated by jasmonate or salicylic acid, suggesting the important regulatory roles of NtPDRs in plant defense and secondary metabolism. They were also responsive to abiotic stresses, like drought and cold, and there was a strong correlation between the presence of promoter cis-elements and abiotic/biotic stress responses. These results provide useful clues for further in-depth studies on the functions of the tobacco PDR genes.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Perfilação da Expressão Gênica/métodos , Mapeamento Físico do Cromossomo/métodos , Tabaco/crescimento & desenvolvimento , Transportadores de Cassetes de Ligação de ATP/química , Cromossomos de Plantas/genética , Ciclopentanos/farmacologia , Evolução Molecular , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Família Multigênica , Oxilipinas/farmacologia , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/genética , Domínios Proteicos , Cimentos de Resina , Ácido Salicílico/farmacologia , Análise de Sequência de RNA , Estresse Fisiológico , Tabaco/efeitos dos fármacos , Tabaco/genética
17.
Nat Metab ; 3(4): 546-557, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33820991

RESUMO

Tissue integrity is contingent on maintaining stem cells. Intestinal stem cells (ISCs) over-proliferate during ageing, leading to tissue dysplasia in Drosophila melanogaster. Here we describe a role for white, encoding the evolutionarily conserved ATP-binding cassette transporter subfamily G, with a particularly well-characterized role in eye colour pigmentation, in ageing-induced ISC proliferation in the midgut. ISCs increase expression of white during ageing. ISC-specific inhibition of white suppresses ageing-induced ISC dysregulation and prolongs lifespan. Of the proteins that form heterodimers with White, Brown mediates ISC dysregulation during ageing. Metabolomics analyses reveal previously unappreciated, profound metabolic impacts of white inhibition on organismal metabolism. Among the metabolites affected by White, tetrahydrofolate is transported by White, is accumulated in ISCs during ageing and is indispensable for ageing-induced ISC over-proliferation. Since Thomas Morgan's isolation of a white mutant as the first Drosophila mutant, white mutants have been used extensively as genetic systems and often as controls. Our findings provide insights into metabolic regulation of stem cells mediated by the classic gene white.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/fisiologia , Envelhecimento/genética , Envelhecimento/fisiologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Proteínas do Olho/genética , Proteínas do Olho/fisiologia , Homeostase/genética , Homeostase/fisiologia , Intestinos/fisiologia , Células-Tronco/fisiologia , Animais , Proliferação de Células , Drosophila melanogaster/genética , Cor de Olho/genética , Ácido Fólico/metabolismo , Intestinos/citologia , Intestinos/crescimento & desenvolvimento , Metabolômica
18.
Int J Mol Sci ; 22(6)2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33801148

RESUMO

Chemotherapeutics are the mainstay treatment for metastatic breast cancers. However, the chemotherapeutic failure caused by multidrug resistance (MDR) remains a pivotal obstacle to effective chemotherapies of breast cancer. Although in vitro evidence suggests that the overexpression of ATP-Binding Cassette (ABC) transporters confers resistance to cytotoxic and molecularly targeted chemotherapies by reducing the intracellular accumulation of active moieties, the clinical trials that target ABCB1 to reverse drug resistance have been disappointing. Nevertheless, studies indicate that ABC transporters may contribute to breast cancer development and metastasis independent of their efflux function. A broader and more clarified understanding of the functions and roles of ABC transporters in breast cancer biology will potentially contribute to stratifying patients for precision regimens and promote the development of novel therapies. Herein, we summarise the current knowledge relating to the mechanisms, functions and regulations of ABC transporters, with a focus on the roles of ABC transporters in breast cancer chemoresistance, progression and metastasis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/classificação , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Progressão da Doença , Suscetibilidade a Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Família Multigênica , Metástase Neoplásica , Estadiamento de Neoplasias , Relação Estrutura-Atividade
19.
Eur J Pharm Sci ; 163: 105854, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33865975

RESUMO

Ciprofloxacin is a commonly prescribed fluoroquinolone antibiotic which is cleared by active tubular secretion and intestinal excretion. Ciprofloxacin is a known substrate of the ATP-binding cassette (ABC) transporters breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 4 (MRP4). In this work, we used positron emission tomography (PET) imaging to investigate the influence of BCRP, MRP4, MRP2 and P-glycoprotein (P-gp) on the excretion of [18F]ciprofloxacin in mice. Dynamic 90-min PET scans were performed after intravenous injection of [18F]ciprofloxacin in wild-type mice without and with pre-treatment with the broad-spectrum MRP inhibitor MK571. Moreover, [18F]ciprofloxacin PET scans were performed in Abcc4(-/-), Abcc2(-/-), Abcc4(-/-)Abcg2(-/-) and Abcb1a/b(-/-)Abcg2(-/-) mice. In addition to non-compartmental pharmacokinetic (PK) analysis, a novel three-compartment PK model was developed for a detailed assessment of the renal disposition of [18F]ciprofloxacin. In MK571 pre-treated mice, a significant increase in the blood exposure to [18F]ciprofloxacin was observed along with a significant reduction in the renal and intestinal clearances. PK modelling revealed a significant reduction in renal radioactivity uptake (CL1) and in the rate constants for transfer of radioactivity from the corticomedullary renal region into blood (k2) and urine (k3), respectively, after MK571 administration. No changes in the renal clearance or in the estimated kidney PK model parameters were observed in any of the studied knockout models, while a significant reduction in the intestinal clearance was observed in Abcc2(-/-) and Abcc4(-/-)Abcg2(-/-) mice. Our data failed to reveal a role of any of the studied ABC transporters in the tubular secretion of ciprofloxacin. This may indicate that ciprofloxacin is handled in the kidneys by more than one transporter family, most likely with a great degree of mutual functional redundancy. Our study highlights the potential of PET imaging for an assessment of transporter-mediated renal excretion of radiolabelled drugs.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Ciprofloxacina , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Camundongos , Camundongos Knockout , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/metabolismo , Tomografia por Emissão de Pósitrons
20.
BMC Ophthalmol ; 21(1): 168, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33836713

RESUMO

BACKGROUND: We present 3 members of a family with macular dystrophy, originally diagnosed as Stargardt disease, with a significantly variable age at onset, caused by a heterozygous mutation in CRX. CASE PRESENTATION: A 43-year-old female with bull's eye maculopathy, whose sister was diagnosed with Stargardt disease previously at another centre, was found to have a single ABCA4 variant. Further examination of the family revealed that the asymptomatic father was also affected, indicating a dominant pattern of inheritance. In addition, the ABCA4 variant was not identified in the sister originally diagnosed with Stargardt disease. Next generation sequencing identified a heterozygous c.121C > T, p.R41W missense mutation in CRX in all 3 affected members. CONCLUSIONS: We describe a common phenotype, but with variable age at onset, with autosomal dominant inheritance and reduced penetrance in a family found to have a pathogenic sequence variant in CRX. This illustrates the importance of panel based molecular genetic testing accompanied by family studies to establish a definitive diagnosis.


Assuntos
Degeneração Macular , Distrofias Retinianas , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Mutação , Linhagem , Fenótipo , Doença de Stargardt
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