Biochim. Biophys. Acta [JOURNAL]
Sun
200 papers
Comparative higher-order structure analysis of antibody biosimilars using combined bottom-up and top-down hydrogen-deuterium exchange mass spectrometry.
Pan J, Zhang S, Borchers CH
Biochim Biophys Acta · 2016 Dec · PMID 27569733 · Publisher ↗
Hydrogen/deuterium exchange (HDX) coupled with mass spectrometry (MS) is a powerful technique for higher-order structural characterization of antibodies. Although the peptide-based bottom-up HDX approach and the protein-...
Hydrogen/deuterium exchange (HDX) coupled with mass spectrometry (MS) is a powerful technique for higher-order structural characterization of antibodies. Although the peptide-based bottom-up HDX approach and the protein-based top-down HDX approach have complementary advantages, the work done so far on biosimilars has involved only one or the other approach. Herein we have characterized the structures of two bevacizumab (BEV) biosimilars and compared them to the reference BEV using both methods. A sequence coverage of 87% was obtained for the heavy chain and 74% for the light chain in the bottom-up approach. The deuterium incorporation behavior of the peptic peptides from the three BEVs were compared side by side and showed no differences at various HDX time points. Top-down experiments were carried out using subzero temperature LC-MS, and the deuterium incorporation of the intact light chain and heavy chain were obtained. Top-down ETD was also performed to obtain amino acid-level HDX information that covered 100% of the light chain, but only 50% coverage is possible for the heavy chain. Consistent with the intact subunit level data, no differences were observed in the amino acid level HDX data. All these results indicate that there are no differences between the three BEV samples with respect to their high-order structures. The peptide level information from the bottom-up approach, and the residue level and intact subunit level information from the top-down approach were complementary and covered the entire antibody.
Vitamin D-dependent chromatin association of CTCF in human monocytes.
Neme A, Seuter S, Carlberg C
Biochim Biophys Acta · 2016 Nov · PMID 27569350 · Publisher ↗
CCCTC-binding factor (CTCF) is a transcription factor being involved in 3D chromatin organization and displays a highly conserved genome-wide binding pattern. In this study, we report the cistrome of CTCF in THP-1 human...
CCCTC-binding factor (CTCF) is a transcription factor being involved in 3D chromatin organization and displays a highly conserved genome-wide binding pattern. In this study, we report the cistrome of CTCF in THP-1 human monocytes and confirm that from the 40,078 CTCF binding sites nearly 85% are identical with those found in K562 monocytes. Quadruplicate chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that at 2130 loci the association strenght of CTCF with genomic DNA was significantly (p<0.05) modulated by stimulation with the natural vitamin D receptor (VDR) ligand 1α,25-dihydroxyvitamin D (1,25(OH)D). Some 55% of these CTCF sites contribute to DNA looping and mark the anchors of 587 putative topologically associating domains (TADs) containing at least one VDR binding site and one 1,25(OH)D target gene. These TADs can explain the regulatory scenarios of up to 70% of all 1,25(OH)D target genes. A self-organizing map approach subdivided the vitamin D-sensitive CTCF sites into seven classes that can be distinguished by participation in DNA loop formation, binding to open chromatin, carrying binding motifs for CTCF or its relative BORIS, overlap with transcription start site (TSS) regions and binding of VDR. These variant molecular profiles suggest different mechanisms of the 1,25(OH)D-dependent action of CTCF. The co-location of VDR and 1,25(OH)D-dependent CTCF sites increases in the context of accessible chromatin and TSS regions but does not show any significant correlation with classical DNA binding mechanisms of CTCF. In conclusion, vitamin D-sensitive CTCF sites provide further mechanistic details to the epigenome-wide understanding of 1,25(OH)D-mediated gene regulation.
Structural and functional characterization of the phosphoglucomutase from Xanthomonas citri subsp. citri.
Goto LS, Vessoni Alexandrino A, Malvessi Pereira C … +4 more , Silva Martins C, D'Muniz Pereira H, Brandão-Neto J, Marques Novo-Mansur MT
Biochim Biophys Acta · 2016 Dec · PMID 27567706 · Publisher ↗
Citrus canker, caused by bacteria Xanthomonas citri subsp. citri, can affect all economically important varieties of citrus. Studying Xanthomonas genes related to the invasive capacity may improve the knowledge on how th...
Citrus canker, caused by bacteria Xanthomonas citri subsp. citri, can affect all economically important varieties of citrus. Studying Xanthomonas genes related to the invasive capacity may improve the knowledge on how this works and ultimately use the information to avoid the disease. Some annotated genes from Xanthomonas citri subsp. citri published genome are addressed to an interesting class of genes named "pathogenicity, virulence and adaptation". One of them is xanA, which encodes a predicted phosphoglucomutase. Phosphoglucomutases are ubiquitous enzymes among the living kingdoms that play roles in carbohydrate metabolism, catalyzing the reversible conversion of 1- to 6-phosphoglucose. In Xanthomonas, phosphoglucomutase activity is required to synthesize precursors of the pathogenesis-related polysaccharide xanthan. In this work, a characterization of this gene product is presented by structural and functional studies. Molecular cloning was used for heterologous expression and deletion of xanA. A Michaelis-Menten kinetics model was obtained using the recombinant protein. The protein structure was also determined by X-ray diffraction on the recombinant enzyme substrate-free, bound to glucose-1,6-biphosphate and to glucose-1-phosphate. Deletion of xanA was done with a suicide plasmid construct and the obtained mutant was tested for pathogenic capacity. This study is the first describing the properties of the Xanthomonas citri subsp. citri phosphoglucomutase.
Y-box-binding protein 1 as a non-canonical factor of base excision repair.
Alemasova EE, Moor NA, Naumenko KN … +4 more , Kutuzov MM, Sukhanova MV, Pestryakov PE, Lavrik OI
Biochim Biophys Acta · 2016 Dec · PMID 27544639 · Publisher ↗
Base excision repair (BER) is a flagship DNA repair system responsible for maintaining genome integrity. Apart from basal enzymes, this system involves several accessory factors essential for coordination and regulation...
Base excision repair (BER) is a flagship DNA repair system responsible for maintaining genome integrity. Apart from basal enzymes, this system involves several accessory factors essential for coordination and regulation of DNA processing during substrate channeling. Y-box-binding protein 1 (YB-1), a multifunctional factor that can interact with DNA, RNA, poly(ADP-ribose) and plenty of proteins including DNA repair enzymes, is increasingly considered as a non-canonical protein of BER. Here we provide quantitative characterization of YB-1 physical interactions with key BER factors such as PARP1, PARP2, APE1, NEIL1 and pol β and comparison of the full-length YB-1 and its C-terminally truncated nuclear form in regard to their binding affinities for BER proteins. Data on functional interactions reveal strong stimulation of PARP1 autopoly(ADP-ribosyl)ation and inhibition of poly(ADP-ribose) degradation by PARG in the presence of YB-1. Moreover, YB-1 is shown to stimulate AP lyase activity of NEIL1 and to inhibit dRP lyase activity of pol β on model DNA duplex structure. We also demonstrate for the first time YB-1 poly(ADP-ribosyl)ation in the presence of RNA.
RBM4-Nova1-SRSF6 splicing cascade modulates the development of brown adipocytes.
Lin JC, Chi YL, Peng HY … +1 more , Lu YH
Biochim Biophys Acta · 2016 Nov · PMID 27535496 · Publisher ↗
Alternative splicing (AS) is a pivotal mechanism for the expansion of gene diversity, which determines the cellular fate or specification. However, the effect of AS networks on brown adipogenesis has not been comprehensi...
Alternative splicing (AS) is a pivotal mechanism for the expansion of gene diversity, which determines the cellular fate or specification. However, the effect of AS networks on brown adipogenesis has not been comprehensively investigated. In this study, we identified the discriminative splicing profiles of RNA-binding motif protein 4a-knockout (RBM4a) brown adipocytes (BAs) and compared them with those of their wild-type counterparts through deep RNA-sequencing. Among these candidates, RBM4a ablation enhanced the relative level of exon 4-excluded neuro-oncological ventral antigen 1 (Nova1) transcripts, which were predominantly generated in embryonic BAs. By contrast, most of the Nova1 transcripts were exon 4-included (Nova1) in mature BAs. The Nova1 isoforms exhibited differential effects on repressing the development of BAs. Moreover, overexpression of Nova1 proteins reduced the serine/arginine splicing factor 6 (SRSF6) level by enhancing the generation of intron 2-included (SRSF6) transcripts, which are a putative candidate of the AS-coupled nonsense-mediated decay mechanism. Furthermore, we observed the positive effect of SRSF6 on BA development. These results highlight the hierarchical role of RBM4a in an AS cascade that manipulates brown adipogenesis.
RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.
Barutcu AR, Hong D, Lajoie BR … +7 more , McCord RP, van Wijnen AJ, Lian JB, Stein JL, Dekker J, Imbalzano AN, Stein GS
Biochim Biophys Acta · 2016 Nov · PMID 27514584 · Full text
RUNX1 is a transcription factor functioning both as an oncogene and a tumor suppressor in breast cancer. RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes. In this study, we e...
RUNX1 is a transcription factor functioning both as an oncogene and a tumor suppressor in breast cancer. RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes. In this study, we examined the relationship between RUNX1-mediated transcription and genome organization. We characterized genome-wide RUNX1 localization and performed RNA-seq and Hi-C in RUNX1-depleted and control MCF-7 breast cancer cells. RNA-seq analysis showed that RUNX1 depletion led to up-regulation of genes associated with chromatin structure and down-regulation of genes related to extracellular matrix biology, as well as NEAT1 and MALAT1 lncRNAs. Our ChIP-Seq analysis supports a prominent role for RUNX1 in transcriptional activation. About 30% of all RUNX1 binding sites were intergenic, indicating diverse roles in promoter and enhancer regulation and suggesting additional functions for RUNX1. Hi-C analysis of RUNX1-depleted cells demonstrated that overall three-dimensional genome organization is largely intact, but indicated enhanced association of RUNX1 near Topologically Associating Domain (TAD) boundaries and alterations in long-range interactions. These results suggest an architectural role for RUNX1 in fine-tuning local interactions rather than in global organization. Our results provide novel insight into RUNX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNX1-dependent compromised gene expression in breast cancer cells.
Enhancer decommissioning by Snail1-induced competitive displacement of TCF7L2 and down-regulation of transcriptional activators results in EPHB2 silencing.
Schnappauf O, Beyes S, Dertmann A … +7 more , Freihen V, Frey P, Jägle S, Rose K, Michoel T, Grosschedl R, Hecht A
Biochim Biophys Acta · 2016 Nov · PMID 27504909 · Publisher ↗
Transcriptional silencing is a major cause for the inactivation of tumor suppressor genes, however, the underlying mechanisms are only poorly understood. The EPHB2 gene encodes a receptor tyrosine kinase that controls ep...
Transcriptional silencing is a major cause for the inactivation of tumor suppressor genes, however, the underlying mechanisms are only poorly understood. The EPHB2 gene encodes a receptor tyrosine kinase that controls epithelial cell migration and allocation in intestinal crypts. Through its ability to restrict cell spreading, EPHB2 functions as a tumor suppressor in colorectal cancer whose expression is frequently lost as tumors progress to the carcinoma stage. Previously we reported that EPHB2 expression depends on a transcriptional enhancer whose activity is diminished in EPHB2 non-expressing cells. Here we investigated the mechanisms that lead to EPHB2 enhancer inactivation. We show that expression of EPHB2 and SNAIL1 - an inducer of epithelial-mesenchymal transition (EMT) - is anti-correlated in colorectal cancer cell lines and tumors. In a cellular model of Snail1-induced EMT, we observe that features of active chromatin at the EPHB2 enhancer are diminished upon expression of murine Snail1. We identify the transcription factors FOXA1, MYB, CDX2 and TCF7L2 as EPHB2 enhancer factors and demonstrate that Snail1 indirectly inactivates the EPHB2 enhancer by downregulation of FOXA1 and MYB. In addition, Snail1 induces the expression of Lymphoid enhancer factor 1 (LEF1) which competitively displaces TCF7L2 from the EPHB2 enhancer. In contrast to TCF7L2, however, LEF1 appears to repress the EPHB2 enhancer. Our findings underscore the importance of transcriptional enhancers for gene regulation under physiological and pathological conditions and show that SNAIL1 employs a combinatorial mechanism to inactivate the EPHB2 enhancer based on activator deprivation and competitive displacement of transcription factors.
Temporal control of Dickeya dadantii main virulence gene expression by growth phase-dependent alteration of regulatory nucleoprotein complexes.
Duprey A, Muskhelishvili G, Reverchon S … +1 more , Nasser W
Biochim Biophys Acta · 2016 Nov · PMID 27498372 · Publisher ↗
In bacteria, important genes are often controlled at the transcriptional level by several factors, forming a complex and intertwined web of interactions. Yet, transcriptional regulators are often studied separately and l...
In bacteria, important genes are often controlled at the transcriptional level by several factors, forming a complex and intertwined web of interactions. Yet, transcriptional regulators are often studied separately and little information is available concerning their interactions. In this work, we dissect the regulation of the major virulence gene pelD in D. dadantii by taking into account the effects of individual binding sites for regulatory proteins FIS and CRP, and the impact of a newly discovered divergent promoter div. Using a combination of biochemistry and genetics approaches we provide an unprecedented level of detail on the multifactorial regulation of bacterial transcription. We show that the growth phase dependent regulation of pelD is under the control of changing composition of higher-order nucleoprotein complexes between FIS, CRP, div and pelD during the growth cycle that allow sequential expression of div and pelD in the early and late exponential growth phases, respectively. This work highlights the importance of "orphan" promoters in gene regulation and that the individual binding sites for a regulator can serve several purposes and have different effects on transcription, adding a new level of complexity to bacterial transcriptional regulation.
ATF4 regulates SREBP1c expression to control fatty acids synthesis in 3T3-L1 adipocytes differentiation.
Chen H, Yuan R, Zhang Y … +8 more , Zhang X, Chen L, Zhou X, Yuan Z, Nie Y, Li M, Mo D, Chen Y
Biochim Biophys Acta · 2016 Nov · PMID 27452504 · Publisher ↗
Activating transcription factor 4 (ATF4), which is highly expressed in 3T3-L1 adipocytes after adipogenic induction, is essential for adipocytes differentiation. ATF4 also plays a vital role in regulating fatty acids bio...
Activating transcription factor 4 (ATF4), which is highly expressed in 3T3-L1 adipocytes after adipogenic induction, is essential for adipocytes differentiation. ATF4 also plays a vital role in regulating fatty acids biosynthesis, whereas the detailed mechanism of this process is still unclear. Here we demonstrated that siRNA-based ATF4 depletion in 3T3-L1 adipocytes significantly reduced the accumulation of fatty acids and triglycerides. Moreover, SREBP1c protein, which is an important transcription factor of lipogenesis, appreciably decreased while Srebp1c mRNA increased. Then we identified that ATF4 could maintain SREBP1c protein stability by directly activating the expression of USP7 which deubiquitinates SREBP1c and increases its protein content in cell. Besides, USP7 could restore the synthesis of fatty acids and triglycerides in the absence of ATF4. On the other hand, we found that ATF4 might inhibit the transcription of Srebp1c through TRB3, which is repressed by IBMX and DEX during early adipogenesis. Thus, our data indicate that ATF4 regulates SREBP1c expression to control fatty acids synthesis.
DNA damage induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes β-catenin-mediated invasion.
Im JY, Yoon SH, Kim BK … +5 more , Ban HS, Won KJ, Chung KS, Jung KE, Won M
Biochim Biophys Acta · 2016 Nov · PMID 27412911 · Publisher ↗
DNA damage induced apoptosis suppressor (DDIAS) is an anti-apoptotic protein that promotes cancer cell survival. We previously reported that DDIAS is transcriptionally activated by nuclear factor of activated T cells 2 (...
DNA damage induced apoptosis suppressor (DDIAS) is an anti-apoptotic protein that promotes cancer cell survival. We previously reported that DDIAS is transcriptionally activated by nuclear factor of activated T cells 2 (NFATc1). However, the upstream regulation of DDIAS expression by growth factors has not been studied. Here, we demonstrate that DDIAS expression is induced by extracellular signal-regulated kinase 5 (ERK5) and myocyte enhancer factor 2B (MEF2B) in response to epidermal growth factor (EGF) and that it positively regulates β-catenin signaling in HeLa cells. The genetic or pharmacological inhibition of ERK5 suppressed DDIAS induction following EGF exposure and the overexpression of constitutively active MEK5 (CA-MEK5) enhanced DDIAS expression. In chromatin immunoprecipitation assays, MEF2B, a downstream target of ERK5, exhibited sequence-specific binding to a MEF2 binding site in the DDIAS promoter following treatment with EGF. The overexpression of MEF2B increased the EGF-mediated induction of DDIAS expression, whereas the knockdown of MEF2B impaired this effect. Furthermore, DDIAS promoted invasion by increasing β-catenin expression at the post-translational level in response to EGF, suggesting that DDIAS plays a crucial role in the metastasis of cancer cells by regulating β-catenin expression. It is unlikely that MEF2B and NFATc1 cooperatively regulate DDIAS transcription in response to EGF. Collectively, EGF activates the ERK5/MEF2 pathway, which in turn induces DDIAS expression to promote cancer cell invasion by activating β-catenin target genes.
NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy.
Yang Y, Sauve AA
Biochim Biophys Acta · 2016 Dec · PMID 27374990 · Full text
We survey the historical development of scientific knowledge surrounding Vitamin B3, and describe the active metabolite forms of Vitamin B3, the pyridine dinucleotides NAD and NADP which are essential to cellular process...
We survey the historical development of scientific knowledge surrounding Vitamin B3, and describe the active metabolite forms of Vitamin B3, the pyridine dinucleotides NAD and NADP which are essential to cellular processes of energy metabolism, cell protection and biosynthesis. The study of NAD has become reinvigorated by new understandings that dynamics within NAD metabolism trigger major signaling processes coupled to effectors (sirtuins, PARPs, and CD38) that reprogram cellular metabolism using NAD as an effector substrate. Cellular adaptations include stimulation of mitochondrial biogenesis, a process fundamental to adjusting cellular and tissue physiology to reduced nutrient availability and/or increased energy demand. Several mammalian metabolic pathways converge to NAD, including tryptophan-derived de novo pathways, nicotinamide salvage pathways, nicotinic acid salvage and nucleoside salvage pathways incorporating nicotinamide riboside and nicotinic acid riboside. Key discoveries highlight a therapeutic potential for targeting NAD biosynthetic pathways for treatment of human diseases. A recent emergence of understanding that NAD homeostasis is vulnerable to aging and disease processes has stimulated testing to determine if replenishment or augmentation of cellular or tissue NAD can have ameliorative effects on aging or disease phenotypes. This experimental approach has provided several proofs of concept successes demonstrating that replenishment or augmentation of NAD concentrations can provide ameliorative or curative benefits. Thus NAD metabolic pathways can provide key biomarkers and parameters for assessing and modulating organism health.
Distinct and overlapping DNMT1 interactions with multiple transcription factors in erythroid cells: Evidence for co-repressor functions.
Papageorgiou DN, Karkoulia E, Amaral-Psarris A … +6 more , Burda P, Kolodziej K, Demmers J, Bungert J, Stopka T, Strouboulis J
Biochim Biophys Acta · 2016 Dec · PMID 27693117 · Publisher ↗
DNMT1 is the maintenance DNA methyltransferase shown to be essential for embryonic development and cellular growth and differentiation in many somatic tissues in mammals. Increasing evidence has also suggested a role for...
DNMT1 is the maintenance DNA methyltransferase shown to be essential for embryonic development and cellular growth and differentiation in many somatic tissues in mammals. Increasing evidence has also suggested a role for DNMT1 in repressing gene expression through interactions with specific transcription factors. Previously, we identified DNMT1 as an interacting partner of the TR2/TR4 nuclear receptor heterodimer in erythroid cells, implicated in the developmental silencing of fetal β-type globin genes in the adult stage of human erythropoiesis. Here, we extended this work by using a biotinylation tagging approach to characterize DNMT1 protein complexes in mouse erythroleukemic cells. We identified novel DNMT1 interactions with several hematopoietic transcription factors with essential roles in erythroid differentiation, including GATA1, GFI-1b and FOG-1. We provide evidence for DNMT1 forming distinct protein subcomplexes with specific transcription factors and propose the existence of a "core" DNMT1 complex with the transcription factors ZBP-89 and ZNF143, which is also present in non-hematopoietic cells. Furthermore, we identified the short (17a.a.) PCNA Binding Domain (PBD) located near the N-terminus of DNMT1 as being necessary for mediating interactions with the transcription factors described herein. Lastly, we provide evidence for DNMT1 serving as a co-repressor of ZBP-89 and GATA1 acting through upstream regulatory elements of the PU.1 and GATA1 gene loci.
Preface: Special Issue on Air Pollution.
Ding W, Ghio AJ, Wu W
Biochim Biophys Acta · 2016 Dec · PMID 27640311 · Publisher ↗
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Branched chain amino acid metabolic reprogramming in heart failure.
Sun H, Wang Y
Biochim Biophys Acta · 2016 Dec · PMID 27639835 · Publisher ↗
Metabolic remodeling is a hall-mark of cardiac maturation and pathology. The switch of substrate utilization from glucose to fatty acid is observed during post-natal maturation period in developing heart, but the process...
Metabolic remodeling is a hall-mark of cardiac maturation and pathology. The switch of substrate utilization from glucose to fatty acid is observed during post-natal maturation period in developing heart, but the process is reversed from fatty acids to glucose in the failing hearts across different clinic and experimental models. Majority of the current investigations have been focusing on the regulatory mechanism and functional impact of this metabolic reprogramming involving fatty acids and carbohydrates. Recent progress in metabolomics and transcriptomic analysis, however, revealed another significant remodeled metabolic branch associated with cardiac development and disease, i.e. Branched-Chain Amino Acid (BCAA) catabolism. These findings have established BCAA catabolic deficiency as a novel metabolic feature in failing hearts with potentially significant impact on the progression of pathological remodeling and dysfunction. In this review, we will evaluate the current evidence and potential implication of these discoveries in the context of heart diseases and novel therapies. This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz.
Upregulation of the S1P receptor in metastatic breast cancer cells increases migration and invasion by induction of PGE and EP/EP activation.
Filipenko I, Schwalm S, Reali L … +4 more , Pfeilschifter J, Fabbro D, Huwiler A, Zangemeister-Wittke U
Biochim Biophys Acta · 2016 Nov · PMID 27616330 · Publisher ↗
Breast cancer is one of the most common and devastating malignancies among women worldwide. Recent evidence suggests that malignant progression is also driven by processes involving the sphingolipid molecule sphingosine...
Breast cancer is one of the most common and devastating malignancies among women worldwide. Recent evidence suggests that malignant progression is also driven by processes involving the sphingolipid molecule sphingosine 1-phosphate (S1P) and its binding to cognate receptor subtypes on the cell surface. To investigate the effect of this interaction on the metastatic phenotype, we used the breast cancer cell line MDA-MB-231 and the sublines 4175 and 1833 derived from lung and bone metastases in nude mice, respectively. In both metastatic cell lines expression of the S1P receptor was strongly upregulated compared to the parental cells and correlated with higher S1P-induced intracellular calcium ([Ca]), higher cyclooxygenase (COX)-2 and microsomal prostaglandin (PG) E synthase expression, and consequently with increased PGE synthesis. PGE synthesis was decreased by antagonists and siRNA against S1P and S1P. Moreover, in parental MDA-MB-231 cells overexpression of S1P by cDNA transfection also increased PGE synthesis, but only after treatment with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine, indicating reversible silencing of the COX-2 promoter. Functionally, the metastatic sublines showed enhanced migration and Matrigel invasion in adapted Boyden chamber assays, which further increased by S1P stimulation. This response was abrogated by either S1P antagonism, COX-2 inhibition or PGE receptor 2 (EP) and 4 (EP) antagonism, but not by S1P antagonism. Our data demonstrate that in breast cancer cells overexpression of S1P and its activation by S1P has pro-inflammatory and pro-metastatic potential by inducing COX-2 expression and PGE signaling via EP and EP.
Antagonizing effect of CLPABP on the function of HuR as a regulator of ARE-containing leptin mRNA stability and the effect of its depletion on obesity in old male mouse.
Nishino T, Matsunaga R, Jikihara H … +9 more , Uchida M, Maeda A, Qi G, Abe T, Kiyonari H, Tashiro S, Inagaki-Ohara K, Shimamoto F, Konishi H
Biochim Biophys Acta · 2016 Nov · PMID 27616329 · Publisher ↗
Cardiolipin and phosphatidic acid-binding protein (CLPABP) is a pleckstrin homology domain-containing protein and is localized on the surface of mitochondria of cultured cells as a large protein-RNA complex. To analyze t...
Cardiolipin and phosphatidic acid-binding protein (CLPABP) is a pleckstrin homology domain-containing protein and is localized on the surface of mitochondria of cultured cells as a large protein-RNA complex. To analyze the physiological functions of CLPABP, we established and characterized a CLPABP knockout (KO) mouse. Although expression levels of CLPABP transcripts in the developmental organs were high, CLPABP KO mice were normal at birth and grew normally when young. However, old male mice presented a fatty phenotype, similar to that seen in metabolic syndrome, in parallel with elevated male- and age-dependent CLPABP gene expression. One of the reasons for this obesity in CLPABP KO mice is dependence on increases in leptin concentration in plasma. The leptin transcripts were also upregulated in the adipose tissue of KO mice compared with wild-type (WT) mice. To understand the difference in levels of the transcriptional product, we focused on the effect of CLPABP on the stability of mRNA involving an AU-rich element (ARE) in its 3'UTR dependence on the RNA stabilizer, human antigen R (HuR), which is one of the CLPABP-binding proteins. Increase in stability of ARE-containing mRNAs of leptin by HuR was antagonized by the expression of CLPABP in cultured cells. Depletion of CLPABP disturbed the normal subcellular localization of HuR to stress granules, and overexpression of CLPABP induced instability of leptin mRNA by inhibiting HuR function. Consequently, leptin levels in old male mice might be regulated by CLPABP expression, which might lead to body weight control.
The effect of regulating molecules on the structure of the PPAR-RXR complex.
Amber-Vitos O, Chaturvedi N, Nachliel E … +2 more , Gutman M, Tsfadia Y
Biochim Biophys Acta · 2016 Nov · PMID 27616290 · Publisher ↗
The PPAR-RXR complex is one of the most significant and prevalent regulatory systems, controlling lipid metabolism by gene expression. Both proteins are members of the nuclear hormone receptor family, consisting of a lig...
The PPAR-RXR complex is one of the most significant and prevalent regulatory systems, controlling lipid metabolism by gene expression. Both proteins are members of the nuclear hormone receptor family, consisting of a ligand-binding domain (LBD), a hinge and a DNA binding domain (DBD). The two proteins form a heterodimer in the nucleus. The ligand-free complex interacts with corepressor proteins and blocks the expression of the genes. With the activating ligands and coactivator segments of regulating proteins, the heterodimer becomes active and allows translation of the genes under its control. We implemented model-independent all-atom molecular dynamics simulations for clarifying the structure changes that the activating ligand and the regulatory peptides impose on the PPAR-RXR system, starting with an LBD up to the PPAR-RXR-DNA complex. The simulations were carried out first with an active state of the protein. Once the relaxed state was attained, it was transformed into the inactive-state, the resulting structure was simulated. As the complex alternates between the active-inactive conformations, most of the changes are noticed at the junction area between the two subunits, located on the surface of a long fused helical structure made of H10-H11 of the proteins. The significant differences between the states included enhanced rigidity of the inactive complex, enhancement of tight contacts. The main drive for the transformation is the relocation of the tip of H12 of the PPAR that drives the carboxylate of the C-terminal towards the junction between H10-H11 of the RXR, leading to rearrangement of the main contact zone of the proteins.
WITHDRAWN: Emodin increases expression of insulin-like growth factor binding protein 1 through activation of MEK/ERK/AMPKα and interaction of PPARγ and Sp1 in lung cancer.
Tang Q, Wu J, Zheng F … +2 more , Chen Y, Hann SS
Biochim Biophys Acta · 2016 Sep · PMID 27615428 · Publisher ↗
Due to an error in the publishing process, this article has been withdrawn at the request of the editors. We wish to clarify that this is in no way related to the integrity of the authors. The Publisher apologizes for an...
Due to an error in the publishing process, this article has been withdrawn at the request of the editors. We wish to clarify that this is in no way related to the integrity of the authors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
Post-translational modifications of CD36 (SR-B2): Implications for regulation of myocellular fatty acid uptake.
Luiken JJ, Chanda D, Nabben M … +2 more , Neumann D, Glatz JF
Biochim Biophys Acta · 2016 Dec · PMID 27615427 · Publisher ↗
The membrane-associated protein CD36, now officially designated as SR-B2, is present in various tissues and fulfills multiple cellular functions. In heart and muscle, CD36 is the main (long-chain) fatty acid transporter,...
The membrane-associated protein CD36, now officially designated as SR-B2, is present in various tissues and fulfills multiple cellular functions. In heart and muscle, CD36 is the main (long-chain) fatty acid transporter, regulating myocellular fatty acid uptake via its vesicle-mediated reversible trafficking (recycling) between intracellular membrane compartments and the cell surface. CD36 is subject to various types of post-translational modification. This review focusses on the role of these modifications in further regulation of myocellular fatty acid uptake. Glycosylation, ubiquitination and palmitoylation are involved in regulating CD36 stability, while phosphorylation at extracellular sites affect the rate of fatty acid uptake. In addition, CD36 modification by O-linked N-acetylglucosamine may regulate the translocation of CD36 from endosomes to the cell surface. Acetylation of CD36 has also been reported, but possible effects on CD36 expression and/or functioning have not yet been addressed. Taken together, CD36 is subject to a multitude of post-translational modifications of which their functional implications are beginning to be understood. Moreover, further investigations are needed to disclose whether these post-translational modifications play a role in altered fatty acid uptake rates seen in several pathologies of heart and muscle. This article is part of a special issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck and Jan F.C. Glatz.
Localization of methyl-branched ceramide [EOS] species within the long-periodicity phase in stratum corneum lipid model membranes: A neutron diffraction study.
Eichner A, Sonnenberger S, Dobner B … +3 more , Hauß T, Schroeter A, Neubert RHH
Biochim Biophys Acta · 2016 Nov · PMID 27614192 · Publisher ↗
The outermost layer of the mammalian skin, the stratum corneum (SC), is a very thin structure and realizes simultaneously the main barrier properties. The penetration barrier for xenobiotica is mostly represented by a co...
The outermost layer of the mammalian skin, the stratum corneum (SC), is a very thin structure and realizes simultaneously the main barrier properties. The penetration barrier for xenobiotica is mostly represented by a complex lipid matrix. There is great interest in the subject of getting information about the arrangement of the lipids, which are mainly ceramides (CER), free fatty acids (FFA) and cholesterol (CHOL). SC lipid model membranes containing synthetically derived lipids in a non-physiological ratio were investigated. To compare the study to a former experiment, a methyl-branched ceramide [EOS] species in presence of the ultra-long chain CER[AP], CHOL and behenic acid (23/10/33/33, wt%) was applied. The membrane structure was studied using the very versatile technique of neutron diffraction. We were able to identify a long-periodicity phase (LPP) with a size of 114Å or 118Å with CER[EOS]-br in a ratio of >60wt% of the ceramides. Furthermore, we figured out two additional coexisting short-periodicity phases (SPP) with repeat distances of 48Å and 45Å, respectively. Partial deuterations of CER[EOS]-br and CER[AP] enabled the localization of the molecules within the multiphase system. CER[EOS]-d3 was present in the LPP, but absent in both SPP. CER[AP]-d3 was determined in both short phases but not localized within the LPP. Besides, we revealed influences of humidity and time with respect to the long-periodicity phase.
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