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Downstream Consequences (downstream + consequence)
Selected AbstractsTOGp regulates microtubule assembly and density during mitosis and contributes to chromosome directional instabilityCYTOSKELETON, Issue 8 2009Lynne Cassimeris Abstract TOGp, a member of the XMAP215 MAP family, is required for bipolar mitotic spindle assembly. To understand how TOGp contributes to spindle assembly, we examined microtubule dynamics after depleting TOGp by siRNA. Fluorescence recovery after photobleaching of GFP-tubulin demonstrated that spindle microtubule turnover is slowed two-fold in the absence of TOGp. Consistent with photobleaching results, microtubule regrowth after washout of the microtubule depolymerizing drug nocodazole was slower at the centrosomes and in the vicinity of mitotic chromatin in cells depleted of TOGp. The slower microtubule turnover is likely due to either nucleation or the transitions of dynamic instability because TOGp depletion did not effect the rate of plus end growth, measured by tracking EB1-GFP at microtubule ends. In contrast, microtubule regrowth after nocodazole washout was unaffected by prior depletion of TACC3, a centrosomal protein that interacts with TOGp. Kinetochore fibers in both untreated and TOGp-depleted cells were stable to incubation at 4°C or lysis in buffer containing calcium indicating that stable kinetochore-microtubule attachments are formed in the absence of TOGp. Depletion of TOGp, but not TACC3, reduced kinetochore oscillations during prometaphase/metaphase. Defects in oscillations are not due simply to multipolarity or loss of centrosome focus in the TOGp-depleted cells, since kinetochore oscillations appear normal in cells treated with the proteosome inhibitor MG132, which also results in multipolar spindles and centrosome fragmentation. We hypothesize that TOGp is required for chromosome motility as a downstream consequence of reduced microtubule dynamics and/or density. Cell Motil. Cytoskeleton 2009. © 2009 Wiley-Liss, Inc. [source] Diminished contraction-induced intracellular signaling towards mitochondrial biogenesis in aged skeletal muscleAGING CELL, Issue 4 2009Vladimir Ljubicic Summary The intent of this study was to determine whether aging affects signaling pathways involved in mitochondrial biogenesis in response to a single bout of contractile activity. Acute stimulation (1 Hz, 5 min) of the tibialis anterior (TA) resulted in a greater rate of fatigue in old (36 month), compared to young (6 month) F344XBN rats, which was associated with reduced ATP synthesis and a lower mitochondrial volume. To investigate fiber type-specific signaling, the TA was sectioned into red (RTA) and white (WTA) portions, possessing two- to 2.5-fold differences in mitochondrial content. The expression and contraction-mediated phosphorylation of p38, MKK3/6, CaMKII and AMPK, were assessed. Kinase protein expression tended to be higher in fiber sections with lower mitochondrial content, such as the WTA, relative to the RTA muscle, and this was exaggerated in tissues from senescent, compared to young animals. At rest, kinase activation was generally similar between young and old animals, despite the age-related variations in mitochondrial volume. In response to contractile activity, age did not influence the signaling of these kinases in the high-oxidative RTA muscle. However, in the low-oxidative WTA muscle, contraction-induced kinase activation was attenuated in old animals, despite the greater metabolic stress imposed by contractile activity in this muscle. Thus, the reduction of contraction-evoked kinase phosphorylation in muscle from old animals is fiber type-specific, and depends on factors which are, in part, independent of the metabolic milieu within the contracting fibers. These findings imply that the downstream consequences of kinase signaling are reduced in aging muscle. [source] Proliferative drive and liver carcinogenesis: Too much of a good thing?JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2009Narci C Teoh Abstract There have been innumerable studies published in the attempt to identify gene expression signatures in hepatocellular carcinoma (HCC). When all the regulators and targets of the differentially expressed genes are analyzed from larger studies, the most striking theme is upregulation of mitosis-promoting and cell proliferation genes in HCC compared with ,liver-specific gene clusters' in non-tumorous tissue. A major limitation of expression profiling is that it only provides a ,snapshot' of what is an evolving process and thus cannot distinguish the differences in gene expression that are primary effectors of dysregulated growth from those that represent downstream consequences. The development of HCC in a chronically diseased liver, often referred to as hepatocarcinogenesis, is a multistep process characterized by the progressive accumulation and interplay of genetic alterations causing aberrant growth, malignant transformation of liver parenchymal cells, followed by vascular invasion and metastasis. This review will discuss HCC precursor lesions, draw on the ,proliferation cluster' genes highlighted from HCC expression profiling studies, relate them to a selection of regulatory networks important in liver regeneration, cell cycle control and their potential significance in the pathogenesis of HCC or primary liver cancer. [source] Mitochondrial respiration and respiration-associated proteins in cell lines created through Parkinson's subject mitochondrial transferJOURNAL OF NEUROCHEMISTRY, Issue 3 2010A. Raquel Esteves J. Neurochem. (2010) 113, 674,682. Abstract Parkinson's disease (PD) is associated with perturbed mitochondrial function. Studies of cytoplasmic hybrid (cybrid) cell lines containing mitochondria from PD subjects suggest complex I dysfunction in particular is a relatively upstream biochemical defect. To evaluate potential downstream consequences of PD mitochondrial dysfunction, we used a cybrid approach to model PD mitochondrial dysfunction; our cybrid cell lines were generated via transfer of PD or control subject platelet mitochondria to mtDNA-depleted NT2 cells. To confirm our PD cybrid mitochondria did indeed differ from control cybrid mitochondria we measured complex I Vmax activities. Consistent with other PD cybrid reports, relative to control cybrid cell lines the PD cybrid cell line mean complex I Vmax activity was reduced. In this validated model, we used an oxygen electrode to characterize PD cybrid mitochondrial respiration. Although whole cell basal oxygen consumption was comparable between the PD and control cybrid groups, the proton leak was increased and maximum respiratory capacity was decreased in the PD cybrids. PD cybrids also had reduced SIRT1 phosphorylation, reduced peroxisome proliferator-activated receptor-, coactivator-1, levels, and increased NF-kB activation. We conclude mitochondrial respiration and pathways influenced by aerobic metabolism are altered in NT2 cybrid cell lines generated through transfer of PD subject platelet mitochondria. [source] Fetal programming: Adaptive life-history tactics or making the best of a bad start?AMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 1 2005James Holland Jones Fetal programming is an ontogenetic phenomenon of increasing interest to human biologists. Because the downstream consequences of fetal programming have clear impacts on specific life-history traits (e.g., age at first reproduction and the general age-pattern of reproductive investments), a number of authors have raised the question of the adaptive significance of fetal programming. In this paper, I review in some detail several classical models in life-history theory and discuss their relative merits and weaknesses for human biology. I suggest that an adequate model of human life-history evolution must account for the highly structured nature of the human life cycle, with its late age at first reproduction, large degree of iteroparity, highly overlapping generations, and extensive, post-weaning parental investment. I further suggest that an understanding of stochastic demography is essential for answering the question of the adaptive significance of fetal programming, and specifically the finding of low birth weight on smaller adult body size and earlier age at first reproduction. Using a stage-structured stochastic population model, I show that the downstream consequences of early deprivation may be "making the best of a bad start" rather than an adaptation per se. When a high-investment strategy entails survival costs, the alternate strategy of early reproduction with relatively low investment may have higher fitness than trying to play the high-investment strategy and failing. Am. J. Hum. Biol. 17:22,33, 2005. © 2004 Wiley-Liss, Inc. [source] | ||||||||||