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Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation 总被引:24,自引:0,他引:24
Gatei M Sloper K Sorensen C Syljuäsen R Falck J Hobson K Savage K Lukas J Zhou BB Bartek J Khanna KK 《The Journal of biological chemistry》2003,278(17):14806-14811
In mammals, the ATM (ataxia-telangiectasia-mutated) and ATR (ATM and Rad3-related) protein kinases function as critical regulators of the cellular DNA damage response. The checkpoint functions of ATR and ATM are mediated, in part, by a pair of checkpoint effector kinases termed Chk1 and Chk2. In mammalian cells, evidence has been presented that Chk1 is devoted to the ATR signaling pathway and is modified by ATR in response to replication inhibition and UV-induced damage, whereas Chk2 functions primarily through ATM in response to ionizing radiation (IR), suggesting that Chk2 and Chk1 might have evolved to channel the DNA damage signal from ATM and ATR, respectively. We demonstrate here that the ATR-Chk1 and ATM-Chk2 pathways are not parallel branches of the DNA damage response pathway but instead show a high degree of cross-talk and connectivity. ATM does in fact signal to Chk1 in response to IR. Phosphorylation of Chk1 on Ser-317 in response to IR is ATM-dependent. We also show that functional NBS1 is required for phosphorylation of Chk1, indicating that NBS1 might facilitate the access of Chk1 to ATM at the sites of DNA damage. Abrogation of Chk1 expression by RNA interference resulted in defects in IR-induced S and G(2)/M phase checkpoints; however, the overexpression of phosphorylation site mutant (S317A, S345A or S317A/S345A double mutant) Chk1 failed to interfere with these checkpoints. Surprisingly, the kinase-dead Chk1 (D130A) also failed to abrogate the S and G(2) checkpoint through any obvious dominant negative effect toward endogenous Chk1. Therefore, further studies will be required to assess the contribution made by phosphorylation events to Chk1 regulation. Overall, the data presented in the study challenge the model in which Chk1 only functions downstream from ATR and indicate that ATM does signal to Chk1. In addition, this study also demonstrates that Chk1 is essential for IR-induced inhibition of DNA synthesis and the G(2)/M checkpoint. 相似文献
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Lee SM Wong WP Loong AM Hiong KC Chew SF Ip YK 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2007,177(1):19-29
The objective of this study was to determine the effects of feeding on the excretory nitrogen (N) metabolism of the aquatic
Chinese soft-shelled turtle, Pelodiscus sinensis, with a special emphasis on the role of urea synthesis in ammonia detoxification. P. sinensis is ureogenic and possesses a full complement of ornithine-urea cycle enzymes in its liver. It is primarily ureotelic in water,
and the estimated rate of urea synthesis in unfed animals was equivalent to only 1.5% of the maximal capacity of carbamoyl
phosphate synthetase I (CPS I) in its liver. Approximately 72 h was required for P. sinensis to completely digest a meal of prawn meat. During this period, there were significant increases in ammonia contents in the
stomach at hour 24 and in the intestine between hours 12 and 36, which could be a result of bacterial activities in the intestinal
tract. However, ammonia contents in the liver, muscle, brain and plasma remained unchanged throughout the 72-h post-feeding.
In contrast, at hour 24, urea contents in the stomach, intestine, liver, muscle, brain and plasma increased significantly
by 2.9−, 3.5−, 2.6−, 2.9−, 3.4 and 3.0-fold, respectively. In addition, there was a 3.3- to 8.0−fold increase in the urea
excretion rate between hours 0 and 36 post-feeding, which preceded the increase in ammonia excretion between hours 12 and
48. By hour 48, 68% of the assimilated N from the feed was excreted, 54% of which was excreted as urea-N. The rate of urea
synthesis apparently increased sevenfold during the initial 24 h after feeding, which demanded only 10% of the maximal CPS
I capacity in P. sinensis. The postprandial detoxification of ammonia to urea in P. sinensis effectively prevented postprandial surges in ammonia contents in the plasma and other tissues, as observed in other animals,
during the 72-h period post-feeding. In addition, postprandial ammonia toxicity was ameliorated by increased transamination
and synthesis of certain amino acids in the liver and muscle of P. sinensis. After feeding, a slight but significant increase in the glutamine content occurred in the brain at hour 24, indicating that
the brain might experience a transient increase in ammonia and ammonia was detoxified to glutamine. 相似文献
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Effects of xylene and formaldehyde inhalations on oxidative stress in adult and developing rats livers. 总被引:2,自引:0,他引:2
Cavit Kum Funda Kiral Selim Sekkin Kamil Seyrek Murat Boyacioglu 《Experimental Animals》2007,56(1):35-42
In this study, it was aimed to demonstrate the possible oxidative stress caused by exposure of xylene and formaldehyde (HCHO) on liver tissue, and on body and liver weights in adult as well as developing rats. The rats (96 female Sprague-Dawley) were randomly divided into four groups: embryonic day 1 (Group 1), 1-day-old infantile rats (Group 2), 4-week-old rats (Group 3) and adult rats (Group 4). The animals were exposed to gases of technical xylene (300 ppm), HCHO (6 ppm) or technical xylene + HCHO (150 ppm + 3 ppm), 8 hours per day for 6 weeks. Superoxide dismutase (SOD) and catalase (CAT) activities, and glutathione (GSH) and malondialdehyde (MDA) levels were evaluated. In addition, body and liver weights were determinated. Compared to the control animals, body and liver weights were decreased in the embryonic day 1 group (P < 0.001, P < 0.01, respectively) and the 1-day-old infantile group (P < 0.001). Liver weight was increased in the 4-week-old group (P < 0.01). SOD activities were decreased in the 4-week-old rats exposed to HCHO (P < 0.01). CAT activities increased in the embryonic day 1 group (P < 0.05). GSH levels were decreased in the 1-day-old infantile group (P < 0.01), and MDA levels was increased in the embryonic day 1 group (P < 0.05) as compared with the respective control groups. As to GSH and MDA levels in adult and 4-week-old animals, no statistically significant differences were observed (P > 0.05). The present study indicates that exposures to xylene, HCHO and a mixture of them are toxic to liver tissue, and developing female rats are especially more adversely affected. Furthermore, the results of this study show that adult female rats could better tolerate the adverse effects of these toxic gases. 相似文献
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Alterations of integrin α3β1 may play a role in the development of diabetic nephropathy. We have investigated the effects
of high glucose and angiotensin II on the expression of integrin α3 and β1, and whether these changes are associated with
integrin-linked kinase (ILK) in cultured mouse podocytes. Integrin β1 and ILK mRNA expression and protein production were
rapidly up-regulated in a dose-dependent manner by high glucose and angiotensin II stimulation. ILK mRNA levels in the mouse
podocytes exposed to 30 mmol/l glucose were 1.66, 1.89, and 1.28 times higher than those in control cells at 6, 24, and 72 h
exposure, respectively. ILK mRNA levels in mouse podocytes exposed to 1 nM, 10 nM, and 100 nM angiotensin II for 6 h were
1.38, 1.55, and 1.93 times higher, respectively, than those in control cells. Angiotensin-II-induced integrin β1 and ILK mRNA
expression was significantly inhibited by treatment with losartan (100 μM). In addition, the up-regulation of ILK synthesis
induced by these stimuli was related to β1 integrin synthesis and increased ILK kinase activity. Cell adhesion assay displayed
inhibitory effects when podocytes were exposed to high concentrations of angiotensin II. Interestingly, glucose and angiotensin
II stimulation induced shrinkage of the cell body and elongation of the podocyte processes, a phenotype similar to that of
immature podocytes. In addition, β1 integrin showed higher levels of staining on both the cell membranes and the cell-cell
contact areas. Thus, high glucose and angiotensin II may affect the regulation of the integrin-ILK system in podocytes; this
system may therefore play a role in the pathogenesis of diabetic nephropathy and other renal diseases affecting podocytes.
The results presented in this paper have not been published previously in whole or part, except in abstract form.
This work was supported by grant R01–2002–000–00139–0 from the Basic Research Program of the Korea Science & Engineering Foundation. 相似文献
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