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51.
52.
Zaka R Stokes D Dion AS Kusnierz A Han F Williams CJ 《Arthritis research & therapy》2006,8(6):R164-13
Ank is a multipass transmembrane protein that regulates the cellular transport of inorganic pyrophosphate. In the progressive ankylosis (ank) mouse, a premature termination mutation at glutamic acid 440 results in a phenotype characterized by inappropriate deposition of basic calcium phosphate crystals in skeletal tissues. Mutations in the amino terminus of ANKH, the human homolog of Ank, result in familial calcium pyrophosphate dihydrate deposition disease. It has been hypothesized that these mutations result in a gain-of-function with respect to the elaboration of extracellular inorganic pyrophosphate. To explore this issue in a mineralization-competent system, we stably transduced ATDC5 cells with wild-type Ank as well as with familial chondrocalcinosis-causing Ank mutations. We evaluated the elaboration of inorganic pyrophosphate, the activity of pyrophosphate-modulating enzymes, and the mineralization in the transduced cells. Expression of transduced protein was confirmed by quantitative real-time PCR and by ELISA. Levels of inorganic pyrophosphate were measured, as were the activities of nucleotide pyrophosphatase phosphodiesterase and alkaline phosphatase. We also evaluated the expression of markers of chondrocyte maturation and the nature of the mineralization phase elaborated by transduced cells. The cell line expressing the proline to leucine mutation at position 5 (P5L) consistently displayed higher levels of extracellular inorganic pyrophosphate and higher phosphodiesterase activity than the other transduced lines. During hypertrophy, however, extracellular inorganic pyrophosphate levels were modulated by alkaline phosphatase activity in this cell system, resulting in the deposition of basic calcium phosphate crystals only in all transduced cell lines. Cells overexpressing wild-type Ank displayed a higher level of expression of type X collagen than cells transduced with mutant Ank. Other markers of hypertrophy and terminal differentiation, such as alkaline phosphatase, osteopontin, and runx2, were not significantly different in cells expressing wild-type or mutant Ank in comparison with cells transduced with an empty vector or with untransduced cells. These results suggest that the P5L Ank mutant is capable of demonstrating a gain-of-function with respect to extracellular inorganic pyrophosphate elaboration, but this effect is modified by high levels of expression of alkaline phosphatase in ATDC5 cells during hypertrophy and terminal differentiation, resulting in the deposition of basic calcium phosphate crystals. 相似文献
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54.
Increased mobility of double-strand breaks requires Mec1, Rad9 and the homologous recombination machinery 总被引:1,自引:0,他引:1
Chromatin mobility is thought to facilitate homology search during homologous recombination and to shift damage either towards or away from specialized repair compartments. However, unconstrained mobility of double-strand breaks could also promote deleterious chromosomal translocations. Here we use live time-lapse fluorescence microscopy to track the mobility of damaged DNA in budding yeast. We found that a Rad52-YFP focus formed at an irreparable double-strand break moves in a larger subnuclear volume than the undamaged locus. In contrast, Rad52-YFP bound at damage arising from a protein-DNA adduct shows no increase in movement. Mutant analysis shows that enhanced double-strand-break mobility requires Rad51, the ATPase activity of Rad54, the ATR homologue Mec1 and the DNA-damage-response mediator Rad9. Consistent with a role for movement in the homology-search step of homologous recombination, we show that recombination intermediates take longer to form in cells lacking Rad9. 相似文献
55.
Rodini CO Batista AC Dionísio TJ Santos CF Cunha FQ Lara VS 《Journal of molecular histology》2008,39(3):275-282
The immunopathologic and inflammatory mechanisms involved in periodontal disease (PD) include the participation of host resident,
inflammatory cells and chemical mediators. Metalloproteinases (MMPs) and nitric oxide (NO) play essential role in extracellular
matrix turnover of periodontal tissue destruction. In this study, by means of RT-PCR through semi-quantitative densitometric
scanning methods, the expression of MMPs -2 and -9 and inducible NO synthase (iNOS) was temporally and spatially investigated
during the destructive mechanisms of experimentally induced PD in rats. Samples from different periods were microscopically
analyzed and compared with the contralateral side (control). Our results showed significant expression of MMP-9 and iNOS in
tissues affected by PD, as compared with controls, three days after PD induction, simultaneously with the beginning of alveolar
bone loss. At 7 days post induction, only the MMP-9 mRNA presented a significantly higher expression, as compared with the
respective controls. Thus, in the rat ligature-induced PD, MMP-9 and iNOS might importantly participate in the early stages
of the disease, including inflammatory cell migration, tissue destruction and alveolar bone resorption. Also, we may suggest
that the exuberant presence of PMNs may be related to the important expression of iNOS and MMP-9 found at 3 days post induction. 相似文献
56.
Background
The evolution of complex molecular traits such as disulphide bridges often requires multiple mutations. The intermediate steps in such evolutionary trajectories are likely to be selectively neutral or deleterious. Therefore, large populations and long times may be required to evolve such traits. 相似文献57.
Buffie J. Clodfelder Juliet Emamaullee Dion D. Hepburn Nicole E. Chakov Heather S. Nettles John B. Vincent 《Journal of biological inorganic chemistry》2001,6(5-6):608-617
The chromium-binding oligopeptide chromodulin (also known as low-molecular-weight chromium-binding substance) has been shown to activate the tyrosine kinase activity of the insulin receptor in response to insulin and has been proposed to be part of a novel autoamplification mechanism for insulin signaling. The model requires that Cr3+ be moved from the blood to insulin-sensitive tissues in response to insulin and subsequently be lost in the urine as chromodulin; however, the model has not been tested by in vivo studies. In vivo studies with rats have shown that the iron transport protein transferrin serves as the major chromic ion transport agent and that this transport is stimulated by insulin. The ion is transported to a variety of tissues, while liver and kidneys are the major target. In hepatocytes, chromodulin occurs in appreciable levels in the cytosol and in the nucleus. Apochromodulin levels appear to be maintained under homeostatic control, although the only detectable form of urinary chromium is probably chromodulin. Increases in urinary chromium loss in response to insulin are reflected by increases in chromodulin, establishing a direct link between carbohydrate metabolism and the oligopeptide. 相似文献
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