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Articles by J Du
Total Records ( 10 ) for J Du
  J Du , L Chen and J. Shen
 

This study sought to isolate and identify proteins that interact with centromere-associated protein E (CENP-E), provide new clues for exploring the function of CENP-E in cell cycle control and the pathogenesis of tumor. Yeast two-hybrid screen and regular molecular biologic techniques were undertaken to screen human HeLa cDNA library with the kinetochore binding domain of CENP-E. The bait from the C-terminus of CENP-E was created by subcloning methods to find out optimal candidate proteins that interact with the kinetochore binding domain of CENP-E. Eight novel CENP-E interacting proteins including Homo sapiens Fanconi anemia complementation group A (FANCA) were obtained. In yeast two-hybrid assay, the N-terminal 260 amino acids of FANCA were found to be necessary and sufficient for the interaction with the C-terminus of CENP-E. The interaction was confirmed by in vitro glutathione S-transferase pull-down assay and in vivo co-immunoprecipitation assay. Our finding of the interaction of CENP-E with FANCA demonstrates that CENP-E and FANCA may play important roles in the functional regulation of the mitotic checkpoint signal pathway.

  J Du , Y Li and X. Zhu
 

CENP-F (also named mitosin) is a multifunctional protein of 350 kDa. In interphase, it is a nuclear protein, whereas in M phase it localizes to the kinetochore, the major microtubule-binding structure on chromosomes essential for chromosome segregation. CENP-F is also critical for myocyte differentiation through the interaction with Rb. It binds to ATF4 and negatively regulates the transcriptional activity of ATF4. It is also important for mitotic progression. Here we show that depletion of CENP-F by RNAi markedly downregulated the methylation of histone H3 at K4 and K9. Consistently, association of HP1 with mitotic chromosomes was largely decreased. These results uncover a novel role of CENP-F in regulation of epigenetic modification on histone H3.

  J Du , Y Zhang , Y Liu , Y Li and X. Zhu
 

Cenp-F (also named mitosin) is a 350-kDa human kinetochore protein important for the mitotic progression. It is also a nuclear matrix protein in interphase cells. Here, we showed that overexpression of N-terminal deletion mutants of Cenp-F containing the C-terminal 112 residues induced chromatin condensation into numerous aggregates of varying sizes in interphase nucleus, colocalizing with the exogenous proteins. In situ hybridization using whole chromosome painting probes indicated that the chromatin aggregates were not prematurely condensed individual chromosomes. Neither were they due to apoptosis. We provided evidence showing association of Cenp-F with certain regions of interphase chromatin fibers. Cenp-F associated with the DNA-dependent protein kinase (DNA-PK), a trimeric protein complex critical for genome homeostasis. Moreover, the DNA-PK association activity of Cenp-F mutants correlated with their ability to induce chromatin aggregation. These results imply a role of Cenp-F in organization of interphase chromatin through association and possibly regulation of DNA-PK.

  J. L Wang , X Yang , K Xia , Z. M Hu , L Weng , X Jin , H Jiang , P Zhang , L Shen , J Feng Guo , N li , Y. R Li , L. F Lei , J Zhou , J Du , Y. F Zhou , Q Pan , J Wang , R. Q Li and B. S. Tang
 

Autosomal-dominant spinocerebellar ataxias constitute a large, heterogeneous group of progressive neurodegenerative diseases with multiple types. To date, classical genetic studies have revealed 31 distinct genetic forms of spinocerebellar ataxias and identified 19 causative genes. Traditional positional cloning strategies, however, have limitations for finding causative genes of rare Mendelian disorders. Here, we used a combined strategy of exome sequencing and linkage analysis to identify a novel spinocerebellar ataxia causative gene, TGM6. We sequenced the whole exome of four patients in a Chinese four-generation spinocerebellar ataxia family and identified a missense mutation, c.1550T–G transition (L517W), in exon 10 of TGM6. This change is at a highly conserved position, is predicted to have a functional impact, and completely cosegregated with the phenotype. The exome results were validated using linkage analysis. The mutation we identified using exome sequencing was located in the same region (20p13–12.2) as that identified by linkage analysis, which cross-validated TGM6 as the causative spinocerebellar ataxia gene in this family. We also showed that the causative gene could be mapped by a combined method of linkage analysis and sequencing of one sample from the family. We further confirmed our finding by identifying another missense mutation c.980A–G transition (D327G) in exon seven of TGM6 in an additional spinocerebellar ataxia family, which also cosegregated with the phenotype. Both mutations were absent in 500 normal unaffected individuals of matched geographical ancestry. The finding of TGM6 as a novel causative gene of spinocerebellar ataxia illustrates whole-exome sequencing of affected individuals from one family as an effective and cost efficient method for mapping genes of rare Mendelian disorders and the use of linkage analysis and exome sequencing for further improving efficiency.

  J Du , J Xie , Z Zhang , H Tsujikawa , D Fusco , D Silverman , B Liang and L. Yue
 

Rationale: Cardiac fibrosis contributes to pathogenesis of atrial fibrillation (AF), which is the most commonly sustained arrhythmia and a major cause of morbidity and mortality. Although it has been suggested that Ca2+ signals are involved in fibrosis promotion, the molecular basis of Ca2+ signaling mechanisms and how Ca2+ signals contribute to fibrogenesis remain unknown.

Objective: To determine the molecular mechanisms of Ca2+-permeable channel(s) in human atrial fibroblasts, and to investigate how Ca2+ signals contribute to fibrogenesis in human AF.

Methods and Results: We demonstrate that the transient receptor potential (TRP) melastatin related 7 (TRPM7) is the molecular basis of the major Ca2+-permeable channel in human atrial fibroblasts. Endogenous TRPM7 currents in atrial fibroblasts resemble the biophysical and pharmacological properties of heterologous expressed TRPM7. Knocking down TRPM7 by small hairpin RNA largely eliminates TRPM7 current and Ca2+ influx in atrial fibroblasts. More importantly, atrial fibroblasts from AF patients show a striking upregulation of both TRPM7 currents and Ca2+ influx and are more prone to myofibroblast differentiation, presumably attributable to the enhanced expression of TRPM7. TRPM7 small hairpin RNA markedly reduced basal AF fibroblast differentiation. Transforming growth factor (TGF)-β1, the major stimulator of atrial fibrosis, requires TRPM7-mediated Ca2+ signal for its effect on fibroblast proliferation and differentiation. Furthermore, TGF-β1–induced differentiation of cultured human atrial fibroblasts is well correlated with an increase of TRPM7 expression induced by TGF-β1.

Conclusions: Our results establish that TRPM7 is the major Ca2+-permeable channel in human atrial fibroblasts and likely plays an essential role in TGF-β1–elicited fibrogenesis in human AF.

  M Snyder , J Du and M. Gerstein
 

The revolution in DNA sequencing technologies has now made it feasible to determine the genome sequences of many individuals; i.e., "personal genomes." Genome sequences of cells and tissues from both normal and disease states have been determined. Using current approaches, whole human genome sequences are not typically assembled and determined de novo, but, instead, variations relative to a reference sequence are identified. We discuss the current state of personal genome sequencing, the main steps involved in determining a genome sequence (i.e., identifying single-nucleotide polymorphisms [SNPs] and structural variations [SVs], assembling new sequences, and phasing haplotypes), and the challenges and performance metrics for evaluating the accuracy of the reconstruction. Finally, we consider the possible individual and societal benefits of personal genome sequences.

  Z Tian , C Rizzon , J Du , L Zhu , J. L Bennetzen , S. A Jackson , B. S Gaut and J. Ma
 

In flowering plants, the accumulation of small deletions through unequal homologous recombination (UR) and illegitimate recombination (IR) is proposed to be the major process counteracting genome expansion, which is caused primarily by the periodic amplification of long terminal repeat retrotransposons (LTR-RTs). However, the full suite of evolutionary forces that govern the gain or loss of transposable elements (TEs) and their distribution within a genome remains unclear. Here, we investigated the distribution and structural variation of LTR-RTs in relation to the rates of local genetic recombination (GR) and gene densities in the rice (Oryza sativa) genome. Our data revealed a positive correlation between GR rates and gene densities and negative correlations between LTR-RT densities and both GR and gene densities. The data also indicate a tendency for LTR-RT elements and fragments to be shorter in regions with higher GR rates; the size reduction of LTR-RTs appears to be achieved primarily through solo LTR formation by UR. Comparison of indica and japonica rice revealed patterns and frequencies of LTR-RT gain and loss within different evolutionary timeframes. Different LTR-RT families exhibited variable distribution patterns and structural changes, but overall LTR-RT compositions and genes were organized according to the GR gradients of the genome. Further investigation of non-LTR-RTs and DNA transposons revealed a negative correlation between gene densities and the abundance of DNA transposons and a weak correlation between GR rates and the abundance of long interspersed nuclear elements (LINEs)/short interspersed nuclear elements (SINEs). Together, these observations suggest that GR and gene density play important roles in shaping the dynamic structure of the rice genome.

  J Du , M A Meledeo , Z Wang and H. S Khanna
 

This report provides a perspective on metabolic glycoengineering methodology developed over the past two decades that allows natural sialic acids to be replaced with chemical variants in living cells and animals. Examples are given demonstrating how this technology provides the glycoscientist with chemical tools that are beginning to reproduce Mother Nature's control over complex biological systems – such as the human brain – through subtle modifications in sialic acid chemistry. Several metabolic substrates (e.g., ManNAc, Neu5Ac, and CMP-Neu5Ac analogs) can be used to feed flux into the sialic acid biosynthetic pathway resulting in numerous – and sometime quite unexpected – biological repercussions upon nonnatural sialoside display in cellular glycans. Once on the cell surface, ketone-, azide-, thiol-, or alkyne-modified glycans can be transformed with numerous ligands via bioorthogonal chemoselective ligation reactions, greatly increasing the versatility and potential application of this technology. Recently, sialic acid glycoengineering methodology has been extended to other pathways with analog incorporation now possible in surface-displayed GalNAc and fucose residues as well as nucleocytoplasmic O-GlcNAc-modified proteins. Finally, recent efforts to increase the "druggability" of sugar analogs used in metabolic glycoengineering, which have resulted in unanticipated "scaffold-dependent" activities, are summarized.

  L Liu , J Hou , J Du , R. S Chumanov , Q Xu , Y Ge , J. A Johnson and R. M. Murphy
 

Tg2576 mice produce high levels of beta-amyloid (Aβ) and develop amyloid deposits, but lack neurofibrillary tangles and do not suffer the extensive neuronal cell loss characteristic of Alzheimer's disease. Protection from Aβ toxicity has been attributed to up-regulation of transthyretin (TTR), a normal component of plasma and cerebrospinal fluid. We compared the effect of TTR purified from human plasma (pTTR) with that produced recombinantly (rTTR) on Aβ aggregation and toxicity. pTTR slowed Aβ aggregation but failed to protect primary cortical neurons from Aβ toxicity. In contrast, rTTR accelerated aggregation, while effectively protecting neurons. This inverse correlation between Aβ aggregation kinetics and toxicity is consistent with the hypothesis that soluble intermediates rather than insoluble fibrils are the most toxic Aβ species. We carried out a detailed comparison of pTTR with rTTR to ascertain the probable cause of these different effects. No differences in secondary, tertiary or quaternary structure were detected. However, pTTR differed from rTTR in the extent and nature of modification at Cys10. We hypothesize that differential modification at Cys10 regulates TTR's effect on Aβ aggregation and toxicity.

  J Du , J Xie and L. Yue
 

TRPM2 is a Ca2+-permeable nonselective cation channel that plays important roles in oxidative stress–mediated cell death and inflammation processes. However, how TRPM2 is regulated under physiological and pathological conditions is not fully understood. Here, we report that both intracellular and extracellular protons block TRPM2 by inhibiting channel gating. We demonstrate that external protons block TRPM2 with an IC50 of pHo = 5.3, whereas internal protons inhibit TRPM2 with an IC50 of pHi = 6.7. Extracellular protons inhibit TRPM2 by decreasing single-channel conductance. We identify three titratable residues, H958, D964, and E994, at the outer vestibule of the channel pore that are responsible for pHo sensitivity. Mutations of these residues reduce single-channel conductance, decrease external Ca2+ ([Ca2+]o) affinity, and inhibit [Ca2+]o-mediated TRPM2 gating. These results support the following model: titration of H958, D964, and E994 by external protons inhibits TRPM2 gating by causing conformation change of the channel, and/or by decreasing local Ca2+ concentration at the outer vestibule, therefore reducing [Ca2+]o permeation and inhibiting [Ca2+]o-mediated TRPM2 gating. We find that intracellular protons inhibit TRPM2 by inducing channel closure without changing channel conductance. We identify that D933 located at the C terminus of the S4-S5 linker is responsible for intracellular pH sensitivity. Replacement of Asp933 by Asn933 changes the IC50 from pHi = 6.7 to pHi = 5.5. Moreover, substitution of Asp933 with various residues produces marked changes in proton sensitivity, intracellular ADP ribose/Ca2+ sensitivity, and gating profiles of TRPM2. These results indicate that D933 is not only essential for intracellular pH sensitivity, but it is also crucial for TRPM2 channel gating. Collectively, our findings provide a novel mechanism for TRPM2 modulation as well as molecular determinants for pH regulation of TRPM2. Inhibition of TRPM2 by acidic pH may represent an endogenous mechanism governing TRPM2 gating and its physiological/pathological functions.

 
 
 
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