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51.
mTOR activates the VPS34–UVRAG complex to regulate autolysosomal tubulation and cell survival 下载免费PDF全文
Michael J Munson George FG Allen Rachel Toth David G Campbell John M Lucocq Ian G Ganley 《The EMBO journal》2015,34(17):2272-2290
Lysosomes are essential organelles that function to degrade and recycle unwanted, damaged and toxic biological components. Lysosomes also act as signalling platforms in activating the nutrient‐sensing kinase mTOR. mTOR regulates cellular growth, but it also helps to maintain lysosome identity by initiating lysosomal tubulation through a process termed autophagosome‐lysosome reformation (ALR). Here we identify a lysosomal pool of phosphatidylinositol 3‐phosphate that, when depleted by specific inhibition of the class III phosphoinositide 3‐kinase VPS34, results in prolonged lysosomal tubulation. This tubulation requires mTOR activity, and we identified two direct mTOR phosphorylation sites on UVRAG (S550 and S571) that activate VPS34. Loss of these phosphorylation sites reduced VPS34 lipid kinase activity and resulted in an increase in number and length of lysosomal tubules. In cells in which phosphorylation at these UVRAG sites is disrupted, the result of impaired lysosomal tubulation alongside ALR activation is massive cell death. Our data imply that ALR is critical for cell survival under nutrient stress and that VPS34 is an essential regulatory element in this process. 相似文献
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53.
Molecular imaging of VEGF receptors in angiogenic vasculature with single-chain VEGF-based probes 总被引:7,自引:0,他引:7
Backer MV Levashova Z Patel V Jehning BT Claffey K Blankenberg FG Backer JM 《Nature medicine》2007,13(4):504-509
We describe a new generation of protein-targeted contrast agents for multimodal imaging of the cell-surface receptors for vascular endothelial growth factor (VEGF). These receptors have a key role in angiogenesis and are important targets for drug development. Our probes are based on a single-chain recombinant VEGF expressed with a cysteine-containing tag that allows site-specific labeling with contrast agents for near-infrared fluorescence imaging, single-photon emission computed tomography or positron emission tomography. These probes retain VEGF activities in vitro and undergo selective and highly specific focal uptake into the vasculature of tumors and surrounding host tissue in vivo. The fluorescence contrast agent shows long-term persistence and co-localizes with endothelial cell markers, indicating that internalization is mediated by the receptors. We expect that multimodal imaging of VEGF receptors with these probes will be useful for clinical diagnosis and therapeutic monitoring, and will help to accelerate the development of new angiogenesis-directed drugs and treatments. 相似文献
54.
Mayken W Wadman Ronald P de Vries Stefanie IC Kalkhove Gerrit A Veldink Johannes FG Vliegenthart 《BMC microbiology》2009,9(1):59
Background
Aspergillus niger is an ascomycetous fungus that is known to reproduce through asexual spores, only. Interestingly, recent genome analysis of A. niger has revealed the presence of a full complement of functional genes related to sexual reproduction [1]. An example of such genes are the dioxygenase genes which in Aspergillus nidulans, have been shown to be connected to oxylipin production and regulation of both sexual and asexual sporulation [2–4]. Nevertheless, the presence of sex related genes alone does not confirm sexual sporulation in A. niger. 相似文献55.
Renate B. Schnabel Philipp S. Wild Sandra Wilde Francisco M. Ojeda Andreas Schulz Tanja Zeller Christoph R. Sinning Jan Kunde Karl J. Lackner Thomas Munzel Stefan Blankenberg 《PloS one》2014,9(11)
Background
Different biological pathways have been related to atrial fibrillation (AF). Novel biomarkers capturing inflammation, oxidative stress, and neurohumoral activation have not been investigated comprehensively in AF.Methods and Results
In the population-based Gutenberg Health Study (n = 5000), mean age 56±11 years, 51% males, we measured ten biomarkers representing inflammation (C-reactive protein, fibrinogen), cardiac and vascular function (midregional pro adrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro-B-type natriuretic peptide [Nt-proBNP], sensitive troponin I ultra [TnI ultra], copeptin, and C-terminal pro endothelin-1), and oxidative stress (glutathioneperoxidase-1, myeloperoxidase) in relation to manifest AF (n = 161 cases). Individuals with AF were older, mean age 64.9±8.3, and more often males, 71.4%. In Bonferroni-adjusted multivariable regression analyses strongest associations per standard deviation increase in biomarker concentrations were observed for the natriuretic peptides Nt-proBNP (odds ratio [OR] 2.89, 99.5% confidence interval [CI] 2.14–3.90; P<0.0001), MR-proANP (OR 2.45, 99.5% CI 1.91–3.14; P<0.0001), the vascular function marker MR-proADM (OR 1.54, 99.5% CI 1.20–1.99; P<0.0001), TnI ultra (OR 1.50, 99.5% CI 1.19–1.90; P<0.0001) and. fibrinogen (OR 1.44, 99.5% CI 1.19–1.75; P<0.0001). Based on a model comprising known clinical risk factors for AF, all biomarkers combined resulted in a net reclassification improvement of 0.665 (99.3% CI 0.441–0.888) and an integrated discrimination improvement of >13%.Conclusions
In conclusion, in our large, population-based study, we identified novel biomarkers reflecting vascular function, MR-proADM, inflammation, and myocardial damage, TnI ultra, as related to AF; the strong association of natriuretic peptides was confirmed. Prospective studies need to examine whether risk prediction of AF can be enhanced beyond clinical risk factors using these biomarkers. 相似文献56.
Evolution of androgen-regulated mRNA expression in mouse kidney 总被引:1,自引:0,他引:1
To gain information on the evolution of mammalian gene expression patterns,
we studied the androgen-inducible expression of three kidney mRNAs in
several mouse species (genus Mus). The RP2, ornithine decarboxylase, and
beta-glucuronidase mRNAs have each evolved independently, in that the
pattern of variation among species is unique for each. This suggests a role
for gene-specific, cis-acting genetic elements. Relationships between the
regulatory phenotypes and the species phylogeny suggest that the variations
in hormone-inducible mRNA expression were generated by a series of
independent mutations that occurred in specific lineages, resulting in
modifications of the progenitor phenotype. Alternatively, the variations
may have preexisted within the progenitor population as polymorphisms that
were fixed during establishment of individual lineages. Thus, significant
alterations in the androgen-regulated mRNA phenotype have occurred either
prior to or during speciation within the Mus genus. These alterations are
presumed to be in regulatory sequences that control the expression of the
corresponding genes and their response to testosterone; as such, they
should be useful in further studying the genetic determinants of gene
expression and its evolution.
相似文献
57.
Background
The relationship between divergence of amino-acid sequence and divergence of function among homologous proteins is complex. The assumption that homologs share function – the basis of transfer of annotations in databases – must therefore be regarded with caution. Here, we present a quantitative study of sequence and function divergence, based on the Gene Ontology classification of function. We determined the relationship between sequence divergence and function divergence in 6828 protein families from the PFAM database. Within families there is a broad range of sequence similarity from very closely related proteins – for instance, orthologs in different mammals – to very distantly-related proteins at the limit of reliable recognition of homology. 相似文献58.