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61.
Centrosome function in normal and tumor cells 总被引:4,自引:0,他引:4
Centrosomes nucleate microtubules that form the mitotic spindle and regulate the equal division of chromosomes during cell division. In cancer, centrosomes are often found amplified to greater than two per cell, and these tumor cells frequently have aneuploid genomes. In this review, we will discuss the cellular factors that regulate the proper duplication of the centrosome and how these regulatory steps can lead to abnormal centrosome numbers and abnormal mitoses. In particular, we highlight the newly emerging role of the Breast Cancer 1 (BRCA1) ubiquitin ligase in this process. 相似文献
62.
Renuka P. Sankaran Thierry Huguet Michael A. Grusak 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2009,119(2):241-253
Increasing the amount of bioavailable micronutrients such as iron and zinc in plant foods for human consumption is an international
goal, intended especially for developing countries where micronutrient deficiencies are an ongoing health risk. Legume seeds
have the potential to provide the essential nutrients required by humans, but concentrations of several minerals are low when
compared to other foods. In order to increase seed mineral concentrations, it is important to understand the genes and processes
involved in mineral distribution within the plant. The main objectives of this study were to use a Medicago truncatula recombinant inbred population (Jemalong-6 × DZA 315.16) to determine loci governing seed mineral concentrations, seed mineral
content, and average seed weight, and to use these loci to propose candidate genes whose expression might contribute to these
traits. Ninety-three lines in 2004 and 169 lines in 2006 were grown for seed harvest and subsequent analysis of seed Ca, Cu,
Fe, K, Mg, Mn, P, and Zn concentrations and content. Quantitative trait loci (QTL) cartographer was used to identify QTL using
composite interval mapping (CIM). CIM identified 46 QTL for seed mineral concentration, 26 for seed mineral content, and 3
for average seed weight. At least one QTL was detected for each mineral trait, and colocation of QTL for several minerals
was found in both years. Results comparing seed weight with seed mineral concentration and content QTL demonstrate that seed
size can be an important determinant of seed mineral concentration. The identification, in this model legume, of transgressive
segregation for nearly all the minerals suggests that allelic recombination of relevant mineral-related genes in agronomic
legumes could be a successful strategy to increase seed mineral concentrations above current levels.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
63.
Neeraja Sankaran 《Journal of the history of biology》2010,43(3):571-599
In 1936, Frank Macfarlane Burnet published a paper entitled “Induced lysogenicity and the mutation of bacteriophage within
lysogenic bacteria,” in which he demonstrated that the introduction of a specific bacteriophage into a bacterial strain consistently
and repeatedly imparted a specific property – namely the resistance to a different phage – to the bacterial strain that was
originally susceptible to lysis by that second phage. Burnet’s explanation for this change was that the first phage was causing
a mutation in the bacterium which rendered it and its successive generations of offspring resistant to lysogenicity. At the
time, this idea was a novel one that needed compelling evidence to be accepted. While it is difficult for us today to conceive
of mutations and genes outside the context of DNA as the physico-chemical basis of genes, in the mid 1930s, when this paper
was published, DNA’s role as the carrier of hereditary information had not yet been discovered and genes and mutations were
yet to acquire physical and chemical forms. Also, during that time genes were considered to exist only in organisms capable
of sexual modes of replication and the status of bacteria and viruses as organisms capable of containing genes and manifesting
mutations was still in question. Burnet’s paper counts among those pieces of work that helped dispel the notion that genes,
inheritance and mutations were tied to an organism’s sexual status. In this paper, I analyze the implications of Burnet’s
paper for the understanding of various concepts – such as “mutation,” and “gene,” – at the time it was published, and how
those understandings shaped the development of the meanings of these terms and our modern conceptions thereof. 相似文献
64.
Darren E. Casteel Eric V. Smith-Nguyen Banumathi Sankaran Sung H. Roh Renate B. Pilz Choel Kim 《The Journal of biological chemistry》2010,285(43):32684-32688
Cyclic GMP-dependent protein kinase (PKG) is a key mediator of the nitric oxide/cGMP signaling pathway and plays a central role in regulating cardiovascular and neuronal functions. The N-terminal ∼50 amino acids of the kinase are required for homodimerization and association with isoform-specific PKG-anchoring proteins (GKAPs), which target the kinase to specific substrates. To understand the molecular details of PKG dimerization and gain insight into its association with GKAPs, we solved a crystal structure of the PKG Iβ dimerization/docking domain. Our structure provides molecular details of this unique leucine/isoleucine zipper, revealing specific hydrophobic and ionic interactions that mediate dimerization and demonstrating the topology of the GKAP interaction surface. 相似文献
65.
Introduction
Early detection, assessment of disease progression, and application of an appropriate therapeutic intervention are all important for the care of patients with type 2 diabetes. Currently, however, there is no simple test for early detection of type 2 diabetes. Established diagnostic tests for the disease including oral glucose tolerance, fasting blood glucose, and hemoglobin A1c are relatively late markers where the disease has already progressed. Since blood is in direct contact with many tissues, we hypothesized that pathological tissue changes are likely to be reflected in proteomic profiles of plasma.Methods
Mice were reared either on regular chow or a high-fat diet at weaning and several physiological responses (i.e., weight, fasting plasma glucose and insulin, and glucose tolerance) were monitored at regular time intervals. Plasma was collected at regular intervals for proteomic analysis by two-dimensional gel electrophoresis and subsequent mass spectrometry.Results
Onset of hyperinsulinemia with corresponding glucose intolerance was observed in 2 weeks and fasting blood glucose levels rose significantly after 4 weeks on the high-fat diet. Many proteins were found to exist in multiple forms (isoforms). Levels of some isoforms including plasma retinol binding protein, transthyretin, Apolipoprotein A1, and kininogen showed significant changes as early as 4 weeks which coincided with the very early development of glucose intolerance.Conclusions
These results show that a proteomic approach to study the development of type 2 diabetes may uncover unknown early post-translationally modified diagnostic and/or therapeutic protein targets. 相似文献66.
Mehta P Katta K Krishnaswamy S 《Protein science : a publication of the Protein Society》2004,13(1):295-300
The HNHc (SMART ID: SM00507) domain (SCOP nomenclature: HNH family) can be subclassified into at least eight subsets by iterative refinement of HMM profiles. An initial clustering of 323 proteins containing the HNHc domain helped identify the subsets. The subsets could be differentiated on the basis of the pattern of occurrence of seven defining features. Domain association is also different between the subsets. The subsets show organism as well as domain-based clustering, suggestive of propagation by both duplication and horizontal transfer events. Structure-based sequence analysis of the subsets led to the identification of common structural and sequence motifs in the HNH family with the other three families under the His-Me endonuclease superfamily. 相似文献
67.
K Sankaran D M Kuhn W Lovenberg 《Biochemical and biophysical research communications》1979,89(3):793-799
Certain pyrazolo-steroids are extremely potent anti-inflammatory agents but are predicted to be inactive glucocorticoids on the basis of their structure. However, one representative compound is found to possess a high affinity for cytoplasmic glucocorticoid receptors. The biological activity of this steroid is greater than that predicted from its affinity for receptors. This may be due to an exceptionally slow rate of dissociation of the receptorsteroid complex, which would prevent an accurate determination of the equilibrium affinity constant. 相似文献
68.
Maryam Raeeszadeh-Sarmazdeh Mathew Coban Shivansh Mahajan Alexandra Hockla Banumathi Sankaran Gregory P. Downey Derek C. Radisky Evette S. Radisky 《The Journal of biological chemistry》2022,298(3)
Matrix metalloproteinases (MMPs) have long been known as key drivers in the development and progression of diseases, including cancer and neurodegenerative, cardiovascular, and many other inflammatory and degenerative diseases, making them attractive potential drug targets. Engineering selective inhibitors based upon tissue inhibitors of metalloproteinases (TIMPs), endogenous human proteins that tightly yet nonspecifically bind to the family of MMPs, represents a promising new avenue for therapeutic development. Here, we used a counter-selective screening strategy for directed evolution of yeast-displayed human TIMP-1 to obtain TIMP-1 variants highly selective for the inhibition of MMP-3 in preference over MMP-10. As MMP-3 and MMP-10 are the most similar MMPs in sequence, structure, and function, our results thus clearly demonstrate the capability for engineering full-length TIMP proteins to be highly selective MMP inhibitors. We show using protein crystal structures and models of MMP-3-selective TIMP-1 variants bound to MMP-3 and counter-target MMP-10 how structural alterations within the N-terminal and C-terminal TIMP-1 domains create new favorable and selective interactions with MMP-3 and disrupt unique interactions with MMP-10. While our MMP-3-selective inhibitors may be of interest for future investigation in diseases where this enzyme drives pathology, our platform and screening strategy can be employed for developing selective inhibitors of additional MMPs implicated as therapeutic targets in disease. 相似文献
69.
Cell membrane organization is dynamic and is assumed to have different characteristic length scales. These length scales, which are influenced by lipid and protein composition as well as by the cytoskeleton, can range from below the optical resolution limit (as with rafts or microdomains) to far above the resolution limit (as with capping phenomena or the formation of lipid “platforms”). The measurement of these membrane features poses a significant problem because membrane dynamics are on the millisecond timescale and are thus beyond the time resolution of conventional imaging approaches. Fluorescence correlation spectroscopy (FCS), a widely used spectroscopic technique to measure membrane dynamics, has the required time resolution but lacks imaging capabilities. A promising solution is the recently introduced method known as imaging total internal reflection (ITIR)-FCS, which can probe diffusion phenomena in lipid membranes with good temporal and spatial resolution. In this work, we extend ITIR-FCS to perform ITIR fluorescence cross-correlation spectroscopy (ITIR-FCCS) between pixel areas of arbitrary shape and derive a generalized expression that is applicable to active transport and diffusion. ITIR-FCCS is applied to model systems exhibiting diffusion, active transport, or a combination of the two. To demonstrate its applicability to live cells, we observe the diffusion of a marker, the sphingolipid-binding domain (SBD) derived from the amyloid peptide Aβ, on live neuroblastoma cells. We investigate the organization and dynamics of SBD-bound lipid microdomains under the conditions of cholesterol removal and cytoskeleton disruption. 相似文献
70.
T cell effector function and anergy avoidance are quantitatively linked to cell division 总被引:8,自引:0,他引:8
Wells AD Walsh MC Sankaran D Turka LA 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(5):2432-2443
We have shown previously that T cells activated by optimal TCR and CD28 ligation exhibit marked proliferative heterogeneity, and approximately 40% of these activated cells fail entirely to participate in clonal expansion. To address how prior cell division influences the subsequent function of primary T cells at the single cell level, primary CD4+ T cells were subjected to polyclonal stimulation, sorted based on the number of cell divisions they had undergone, and restimulated by ligation of TCR/CD28. We find that individual CD4+ T cells exhibit distinct secondary response patterns that depend upon their prior division history, such that cells that undergo more rounds of division show incrementally greater IL-2 production and proliferation in response to restimulation. CD4+ T cells that fail to divide after activation exist in a profoundly hyporesponsive state that is refractory to both TCR/CD28-mediated and IL-2R-mediated proliferative signals. We find that this anergic state is associated with defects in both TCR-coupled activation of the p42/44 mitogen-activated protein kinase (extracellular signal-related kinase 1/2) and IL-2-mediated down-regulation of the cell cycle inhibitor p27kip1. However, these defects are selective, as TCR-mediated intracellular calcium flux and IL-2R-coupled STAT5 activation remain intact in these cells. Therefore, the process of cell division or cell cycle progression plays an integral role in anergy avoidance in primary T cells, and may represent a driving force in the formation of the effector/memory T cell pool. 相似文献