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Decreased Growth (decreased + growth)
Terms modified by Decreased Growth Selected AbstractsGene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulationGENES, CHROMOSOMES AND CANCER, Issue 4 2008Petra Håkansson Philadelphia (Ph) chromosome-positive leukemia is characterized by the BCR/ABL1 fusion protein that affects a wide range of signal transduction pathways. The knowledge about its downstream target genes is, however, still quite limited. To identify novel BCR/ABL1-regulated genes we used global gene expression profiling of several Ph-positive and Ph-negative cell lines treated with imatinib. Following imatinib treatment, the Ph-positive cells showed decreased growth, viability, and reduced phosphorylation of BCR/ABL1 and STAT5. In total, 142 genes were identified as being dependent on BCR/ABL1-mediated signaling, mainly including genes involved in signal transduction, e.g. the JAK/STAT, MAPK, TGFB, and insulin signaling pathways, and in regulation of metabolism. Interestingly, BCR/ABL1 was found to activate several genes involved in negative feedback regulation (CISH, SOCS2, SOCS3, PIM1, DUSP6, and TNFAIP3), which may act to indirectly suppress the tumor promoting effects exerted by BCR/ABL1. In addition, several genes identified as deregulated upon BCR/ABL1 expression could be assigned to the TGFB and NFkB signaling pathways, as well as to reflect the metabolic adjustments needed for rapidly growing cells. Apart from providing important pathogenetic insights into BCR/ABL1 -mediated leukemogenesis, the present study also provides a number of pathways/individual genes that may provide attractive targets for future development of targeted therapies. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045,2257/suppmat. © 2008 Wiley-Liss, Inc. [source] Inhibition of prolidase activity by nickel causes decreased growth of proline auxotrophic CHO cells,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2005Wojciech Miltyk Abstract Occupational exposure to nickel has been epidemiologically linked to increased cancer risk in the respiratory tract. Nickel-induced cell transformation is associated with both genotoxic and epigenetic mechanisms that are poorly understood. Prolidase [E.C.3.4.13.9] is a cytosolic Mn(II)-activated metalloproteinase that specifically hydrolyzes imidodipeptides with C-terminal proline or hydroxyproline and plays an important role in the recycling of proline for protein synthesis and cell growth. Prolidase also provides free proline as substrate for proline oxidase, whose gene is activated by p53 during apoptosis. The inhibition of prolidase activity by nickel has not yet been studied. We first showed that Ni(II) chloride specifically inhibited prolidase activity in CHO-K1 cells in situ. This interpretation was possible because CHO-K1 cells are proline auxotrophs requiring added free proline or proline released from added Gly-Pro by prolidase. In a dose-dependent fashion, Ni(II) inhibited growth on Gly-Pro but did not inhibit growth on proline, thereby showing inhibition of prolidase in situ in the absence of nonspecific toxicity. Studies using cell-free extracts showed that Ni(II) inhibited prolidase activity when present during prolidase activation with Mn(II) or during incubation with Gly-Pro. In kinetic studies, we found that Ni(II) inhibition of prolidase varied with respect to Mn(II) concentration. Analysis of these data suggested that increasing concentrations of Mn(II) stabilized the enzyme protein against Ni(II) inhibition. Because prolidase is an important enzyme in collagen metabolism, inhibition of the enzyme activity by nickel could alter the metabolism of collagen and other matrix proteins, and thereby alter cell,matrix and cell,cell interactions involved in gene expression, genomic stability, cellular differentiation, and cell proliferation. Published 2005 Wiley-Liss, Inc. [source] The Ozone Component of Global Change: Potential Effects on Agricultural and Horticultural Plant Yield, Product Quality and Interactions with Invasive SpeciesJOURNAL OF INTEGRATIVE PLANT BIOLOGY, Issue 4 2009Fitzgerald Booker The productivity, product quality and competitive ability of important agricultural and horticultural plants in many regions of the world may be adversely affected by current and anticipated concentrations of ground-level ozone (O3). Exposure to elevated O3 typically results in suppressed photosynthesis, accelerated senescence, decreased growth and lower yields. Various approaches used to evaluate O3 effects generally concur that current yield losses range from 5% to 15% among sensitive plants. There is, however, considerable genetic variability in plant responses to O3. To illustrate this, we show that ambient O3 concentrations in the eastern United States cause substantially different levels of damage to otherwise similar snap bean cultivars. Largely undesirable effects of O3 can also occur in seed and fruit chemistry as well as in forage nutritive value, with consequences for animal production. Ozone may alter herbicide efficacy and foster establishment of some invasive species. We conclude that current and projected levels of O3 in many regions worldwide are toxic to sensitive plants of agricultural and horticultural significance. Plant breeding that incorporates O3 sensitivity into selection strategies will be increasingly necessary to achieve sustainable production with changing atmospheric composition, while reductions in O3 precursor emissions will likely benefit world food production and reduce atmospheric concentrations of an important greenhouse gas. [source] Ease and effectiveness of costly autotomy vary with predation intensity among lizard populationsJOURNAL OF ZOOLOGY, Issue 3 2004William E. Cooper Jr Abstract Costly anti-predatory defences are used in ecological time and maintained in evolutionary time by natural selection favouring individuals that survive through their use. Autotomy of expendable body parts is a striking example of a defence having multiple substantial costs, including loss of ability to use the same defence, loss of energy, and decreased growth, reproductive success and survival following autotomy, plus the energetic cost of replacing the lost body part in species capable of regenerating them. Our study shows that autotomy in the lacertid lizard Podarcis lilfordi reduces sprint speed, indicating decreased capacity to escape as well as the loss of energy. Autotomy carries substantial cost, and thus should be avoided except as a last resort. Ease of autotomy and post-autotomic movements were studied in three populations of lacertid lizards. Two were islet populations of P. lilfordi from Aire (lowest predation pressure) and Colom (intermediate predation pressure) off Minorca. The third was a mainland population of Podarcis hispanica, a closely related species from the mainland of the Iberian Peninsula where predation pressure is higher than on the islets. As predicted, a suite of autotomic traits increases the effectiveness of autotomy as a defence as predation pressure increases. With increasing predation pressure, the frequency of voluntary autotomy increases, latency to autotomy decreases, pressure on the tail needed to induce autotomy decreases, vigour of post-autotomic tail movements increases, and distance moved by the shed tail increases. Additional changes that might be related to predation pressure, but could have other causes, are the presence of tail coloration contrasting with body coloration except under the lowest predation pressure (Aire) and longer tails in the mainland species P. hispanica. Correspondence between predation pressure and the suite of autotomic traits suggests that autotomy is an important defence that responds to natural selection. Comparative data are needed to establish the generality of relationships suggested in our study of only three populations. [source] Dissecting the essentiality of the bifunctional trypanothione synthetase-amidase in Trypanosoma brucei using chemical and genetic methodsMOLECULAR MICROBIOLOGY, Issue 3 2009Susan Wyllie Summary The bifunctional trypanothione synthetase-amidase (TRYS) comprises two structurally distinct catalytic domains for synthesis and hydrolysis of trypanothione (N1,N8 - bis(glutathionyl)spermidine). This unique dithiol plays a pivotal role in thiol-redox homeostasis and in defence against chemical and oxidative stress in trypanosomatids. A tetracycline-dependent conditional double knockout of TRYS (cDKO) was generated in bloodstream Trypanosoma brucei. Culture of cDKO parasites without tetracycline induction resulted in loss of trypanothione and accumulation of glutathione, followed by growth inhibition and cell lysis after 6 days. In the absence of inducer, cDKO cells were unable to infect mice, confirming that this enzyme is essential for virulence in vivo as well as in vitro. To establish whether both enzymatic functions were essential, an amidase-dead mutant cDKO line was generated. In the presence of inducer, this line showed decreased growth in vitro and decreased virulence in vivo, indicating that the amidase function is not absolutely required for viability. The druggability of TRYS was assessed using a potent small molecule inhibitor developed in our laboratory. Growth inhibition correlated in rank order cDKO, single KO, wild-type and overexpressing lines and produced the predicted biochemical phenotype. The synthetase function of TRYS is thus unequivocally validated as a drug target by both chemical and genetic methods. 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