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排序方式: 共有401条查询结果,搜索用时 15 毫秒
151.
A Dickinson K Y Yeung J Donoghue M J Baker R DW Kelly M McKenzie T G Johns J C St. John 《Cell death and differentiation》2013,20(12):1644-1653
As stem cells undergo differentiation, mitochondrial DNA (mtDNA) copy number is strictly regulated in order that specialized cells can generate appropriate levels of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) to undertake their specific functions. It is not understood whether tumor-initiating cells regulate their mtDNA in a similar manner or whether mtDNA is essential for tumorigenesis. We show that human neural stem cells (hNSCs) increased their mtDNA content during differentiation in a process that was mediated by a synergistic relationship between the nuclear and mitochondrial genomes and results in increased respiratory capacity. Differentiating multipotent glioblastoma cells failed to match the expansion in mtDNA copy number, patterns of gene expression and increased respiratory capacity observed in hNSCs. Partial depletion of glioblastoma cell mtDNA rescued mtDNA replication events and enhanced cell differentiation. However, prolonged depletion resulted in impaired mtDNA replication, reduced proliferation and induced the expression of early developmental and pro-survival markers including POU class 5 homeobox 1 (OCT4) and sonic hedgehog (SHH). The transfer of glioblastoma cells depleted to varying degrees of their mtDNA content into immunocompromised mice resulted in tumors requiring significantly longer to form compared with non-depleted cells. The number of tumors formed and the time to tumor formation was relative to the degree of mtDNA depletion. The tumors derived from mtDNA depleted glioblastoma cells recovered their mtDNA copy number as part of the tumor formation process. These outcomes demonstrate the importance of mtDNA to the initiation and maintenance of tumorigenesis in glioblastoma multiforme. 相似文献
152.
Anantharam A Bittner MA Aikman RL Stuenkel EL Schmid SL Axelrod D Holz RW 《Molecular biology of the cell》2011,22(11):1907-1918
Dynamin is a master regulator of membrane fission in endocytosis. However, a function for dynamin immediately upon fusion has also been suspected from a variety of experiments that measured release of granule contents. The role of dynamin guanosine triphosphate hydrolase (GTPase) activity in controlling fusion pore expansion and postfusion granule membrane topology was investigated using polarization optics and total internal reflection fluorescence microscopy (pTIRFM) and amperometry. A dynamin-1 (Dyn1) mutant with increased GTPase activity resulted in transient deformations consistent with rapid fusion pore widening after exocytosis; a Dyn1 mutant with decreased activity slowed fusion pore widening by stabilizing postfusion granule membrane deformations. The experiments indicate that, in addition to its role in endocytosis, GTPase activity of dynamin regulates the rapidity of fusion pore expansion from tens of milliseconds to seconds after fusion. These findings expand the membrane-sculpting repertoire of dynamin to include the regulation of immediate postfusion events in exocytosis that control the rate of release of soluble granule contents. 相似文献
153.
Stefano Tiziani Yunyi Kang Ricky Harjanto Joshua Axelrod Carlo Piermarocchi William Roberts Giovanni Paternostro 《PloS one》2013,8(12)
The tumor microenvironment is emerging as an important therapeutic target. Most studies, however, are focused on the protein components, and relatively little is known of how the microenvironmental metabolome might influence tumor survival. In this study, we examined the metabolic profiles of paired bone marrow (BM) and peripheral blood (PB) samples from 10 children with acute lymphoblastic leukemia (ALL). BM and PB samples from the same patient were collected at the time of diagnosis and after 29 days of induction therapy, at which point all patients were in remission. We employed two analytical platforms, high-resolution magnetic resonance spectroscopy and gas chromatography-mass spectrometry, to identify and quantify 102 metabolites in the BM and PB. Standard ALL therapy, which includes l-asparaginase, completely removed circulating asparagine, but not glutamine. Statistical analyses of metabolite correlations and network reconstructions showed that the untreated BM microenvironment was characterized by a significant network-level signature: a cluster of highly correlated lipids and metabolites involved in lipid metabolism (p<0.006). In contrast, the strongest correlations in the BM upon remission were observed among amino acid metabolites and derivatives (p<9.2×10-10). This study provides evidence that metabolic characterization of the cancer niche could generate new hypotheses for the development of cancer therapies. 相似文献
154.
Xu Q Saikatendu KS Krishna SS McMullan D Abdubek P Agarwalla S Ambing E Astakhova T Axelrod HL Carlton D Chiu HJ Clayton T DiDonato M Duan L Elsliger MA Feuerhelm J Grzechnik SK Hale J Hampton E Han GW Haugen J Jaroszewski L Jin KK Klock HE Knuth MW Koesema E Miller MD Morse AT Nigoghossian E Okach L Oommachen S Paulsen J Reyes R Rife CL Schwarzenbacher R van den Bedem H White A Wolf G Hodgson KO Wooley J Deacon AM Godzik A Lesley SA Wilson IA 《Proteins》2007,69(2):433-439
155.
Zubieta C Joseph R Krishna SS McMullan D Kapoor M Axelrod HL Miller MD Abdubek P Acosta C Astakhova T Carlton D Chiu HJ Clayton T Deller MC Duan L Elias Y Elsliger MA Feuerhelm J Grzechnik SK Hale J Han GW Jaroszewski L Jin KK Klock HE Knuth MW Kozbial P Kumar A Marciano D Morse AT Murphy KD Nigoghossian E Okach L Oommachen S Reyes R Rife CL Schimmel P Trout CV van den Bedem H Weekes D White A Xu Q Hodgson KO Wooley J Deacon AM Godzik A Lesley SA Wilson IA 《Proteins》2007,69(2):234-243
TyrA is a member of the dye-decolorizing peroxidase (DyP) family, a new family of heme-dependent peroxidase recently identified in fungi and bacteria. Here, we report the crystal structure of TyrA in complex with iron protoporphyrin (IX) at 2.3 A. TyrA is a dimer, with each monomer exhibiting a two-domain, alpha/beta ferredoxin-like fold. Both domains contribute to the heme-binding site. Co-crystallization in the presence of an excess of iron protoporphyrin (IX) chloride allowed for the unambiguous location of the active site and the specific residues involved in heme binding. The structure reveals a Fe-His-Asp triad essential for heme positioning, as well as a novel conformation of one of the heme propionate moieties compared to plant peroxidases. Structural comparison to the canonical DyP family member, DyP from Thanatephorus cucumeris (Dec 1), demonstrates conservation of this novel heme conformation, as well as residues important for heme binding. Structural comparisons with representative members from all classes of the plant, bacterial, and fungal peroxidase superfamily demonstrate that TyrA, and by extension the DyP family, adopts a fold different from all other structurally characterized heme peroxidases. We propose that a new superfamily be added to the peroxidase classification scheme to encompass the DyP family of heme peroxidases. 相似文献
156.
157.
Tao H Inoue K Kiyonari H Bassuk AG Axelrod JD Sasaki H Aizawa S Ueno N 《Developmental biology》2012,364(2):138-148
The establishment of trophectoderm (TE) manifests as the formation of epithelium, and is dependent on many structural and regulatory components that are commonly found and function in many epithelial tissues. However, the mechanism of TE formation is currently not well understood. Prickle1 (Pk1), a core component of the planar cell polarity (PCP) pathway, is essential for epiblast polarization before gastrulation, yet the roles of Pk family members in early mouse embryogenesis are obscure. Here we found that Pk2(-/-) embryos died at E3.0-3.5 without forming the blastocyst cavity and not maintained epithelial integrity of TE. These phenotypes were due to loss of the apical-basal (AB) polarity that underlies the asymmetric redistribution of microtubule networks and proper accumulation of AB polarity components on each membrane during compaction. In addition, we found GTP-bound active form of nuclear RhoA was decreased in Pk2(-/-) embryos during compaction. We further show that the first cell fate decision was disrupted in Pk2(-/-) embryos. Interestingly, Pk2 localized to the nucleus from the 2-cell to around the 16-cell stage despite its cytoplasmic function previously reported. Inhibiting farnesylation blocked Pk2's nuclear localization and disrupted AB cell polarity, suggesting that Pk2 farnesylation is essential for its nuclear localization and function. The cell polarity phenotype was efficiently rescued by nuclear but not cytoplasmic Pk2, demonstrating the nuclear localization of Pk2 is critical for its function. 相似文献
158.
159.
William T. King Christopher L. Axelrod Elizabeth R.M. Zunica Robert C. Noland Gangarao Davuluri Hisashi Fujioka Bernard Tandler Kathryn Pergola Gerlinda E. Hermann Richard C. Rogers Sandra Lpez-Domnech Wagner S. Dantas Krisztian Stadler Charles L. Hoppel John P. Kirwan 《The Journal of biological chemistry》2021,297(4)
160.