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Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2 下载免费PDF全文
Deng J Lu PD Zhang Y Scheuner D Kaufman RJ Sonenberg N Harding HP Ron D 《Molecular and cellular biology》2004,24(23):10161-10168
Numerous stressful conditions activate kinases that phosphorylate the alpha subunit of translation initiation factor 2 (eIF2alpha), thus attenuating mRNA translation and activating a gene expression program known as the integrated stress response. It has been noted that conditions associated with eIF2alpha phosphorylation, notably accumulation of unfolded proteins in the endoplasmic reticulum (ER), or ER stress, are also associated with activation of nuclear factor kappa B (NF-kappaB) and that eIF2alpha phosphorylation is required for NF-kappaB activation by ER stress. We have used a pharmacologically activable version of pancreatic ER kinase (PERK, an ER stress-responsive eIF2alpha kinase) to uncouple eIF2alpha phosphorylation from stress and found that phosphorylation of eIF2alpha is both necessary and sufficient to activate both NF-kappaB DNA binding and an NF-kappaB reporter gene. eIF2alpha phosphorylation-dependent NF-kappaB activation correlated with decreased levels of the inhibitor IkappaBalpha protein. Unlike canonical signaling pathways that promote IkappaBalpha phosphorylation and degradation, eIF2alpha phosphorylation did not increase phosphorylated IkappaBalpha levels or affect the stability of the protein. Pulse-chase labeling experiments indicate instead that repression of IkappaBalpha translation plays an important role in NF-kappaB activation in cells experiencing high levels of eIF2alpha phosphorylation. These studies suggest a direct role for eIF2alpha phosphorylation-dependent translational control in activating NF-kappaB during ER stress. 相似文献
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BackgroundA number of studies have examined time intervals between care steps in breast cancer diagnosis and treatment. The objective of this study was to document the elapsed time from first clinical or mammographic detection of breast abnormality to initiation of first adjuvant therapy in women with invasive breast cancer in Nova Scotia and to examine the effect of age, disease stage and place of residence on these intervals.MethodsAll dates were abstracted from patient charts and the Oncology Patient Information System. Eligible women were those with invasive breast cancer detected by Sept. 1, 1999, who were referred to 1 of 2 provincial cancer treatment centres by Sept. 1, 2000. All time intervals were calculated in days, and only patients experiencing both care events defining an interval were included in the analysis of time to event for that interval. We used proportional hazards regression analysis to evaluate the influence of patient age, disease stage and place of residence on times between care events.ResultsA total of 776 new diagnoses of breast cancer were reported to the Nova Scotia Cancer Registry over the study period. Of the 776, 467 met the inclusion criteria, and 364 patients were eligible for analysis. The overall median time from clinical or mammographic detection of breast cancer to initiation of first adjuvant therapy was 91 days (interquartile range 72–123 days). Disease stage was the strongest predictor of elapsed time: the median interval from disease detection to initiation of first adjuvant therapy for patients with stage I disease was 118 days, as compared with 85 days for those with stage II disease and 75 days for those with stage III disease (adjusted hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.6–2.8). Patients aged 70 years or more at diagnosis experienced longer elapsed times (median interval 98 days) than did younger patients (93 days for those aged 50–69 years and 82 days for those aged 49 years or less) (adjusted HR 1.6, 95% CI 1.1–2.4).InterpretationWomen aged 70 or more and those with stage I breast cancer experienced longer elapsed times from disease detection to initiation of first adjuvant therapy than did younger women and those with more advanced disease. These findings may have implications for the design of interventions to minimize intervals between steps in breast cancer care and should be validated within the Canadian context. Future investigation exploring the full spectrum of breast cancer care may lead to a more complete understanding of processes and gaps in the current system.Time intervals for isolated care steps in the diagnosis and management of breast cancer have been evaluated in a number of publications from Canada, Germany and the United Kingdom. These studies have focused on time to first surgical intervention,1 time to pathological confirmation of invasive disease2 or a composite interval spanning onset of symptoms to initiation of first treatment, which, in the vast majority of cases, is surgical intervention.3,4,5,6 The spectrum of care for potentially curable breast cancer, however, extends from initial detection to completion of all adjuvant therapies and has become increasingly complex and multidisciplinary. Patients interact with a sequence of various health care professionals and undergo a series of procedures at various medical facilities or in different areas of a large hospital. Most patients are referred for 1 or more adjuvant therapies (radiation, chemotherapy or hormonal therapy), all of which have been shown to reduce the risk of locally recurrent or metastatic disease and to improve overall survival in appropriately selected patients.7,8,9 Although the time from referral to initiation of adjuvant therapy is a critical component in breast cancer care, it has not been included in previous analyses of elapsed times in breast cancer care.The first objective of our study was to document elapsed times from date of mammographic or clinical detection of breast abnormality to initiation of first adjuvant therapy for women with invasive breast cancer. Our second objective was to examine the influence of age, disease stage and place of residence at the time of diagnosis on this elapsed time. 相似文献
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Sajan MP Standaert ML Miura A Kahn CR Farese RV 《Molecular endocrinology (Baltimore, Md.)》2004,18(10):2513-2521
Insulin receptor substrates (IRSs) 1 and 2 are postulated to control the activation of phosphatidylinositol 3-kinase (PI3K)-dependent signaling factors, namely, atypical protein kinase C (aPKC) and protein kinase B (PKB)/Akt, which mediate metabolic effects of insulin. However, it is uncertain whether aPKC and PKB are activated together or differentially in response to IRS-1 and IRS-2 activation in insulin-sensitive tissues. Presently, we examined insulin activation of aPKC and PKB in vastus lateralis muscle, adipocytes, and liver in wild-type and IRS-1 knockout mice, and observed striking tissue-specific differences. In muscle of IRS-1 knockout mice, the activation of both aPKC and PKB was markedly diminished. In marked contrast, only aPKC activation was diminished in adipocytes, and only PKB activation was diminished in liver. These results suggest that IRS-1 is required for: 1) activation of both aPKC and PKB in muscle; 2) aPKC, but not PKB, activation in adipocytes; and 3) PKB, but not aPKC, activation in liver. Presumably, IRS-2 or other PI3K activators account for the normal activation of aPKC in liver and PKB in adipocytes of IRS-1 knockout mice. These complexities in aPKC and PKB activation may be relevant to metabolic abnormalities seen in tissues in which IRS-1 or IRS-2 is specifically or predominantly down-regulated. 相似文献
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Spontaneous neural activity is required for the establishment and maintenance of the olfactory sensory map 总被引:3,自引:0,他引:3
We have developed a genetic approach to examine the role of spontaneous activity and synaptic release in the establishment and maintenance of an olfactory sensory map. Conditional expression of tetanus toxin light chain, a molecule that inhibits synaptic release, does not perturb targeting during development, but neurons that express this molecule in a competitive environment fail to maintain appropriate synaptic connections and disappear. Overexpression of the inward rectifying potassium channel, Kir2.1, diminishes the excitability of sensory neurons and more severely disrupts the formation of an olfactory map. These studies suggest that spontaneous neural activity is required for the establishment and maintenance of the precise connectivity inherent in an olfactory sensory map. 相似文献
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Rommers JM Meijerhof R Noordhuizen JP Kemp B 《Reproduction, nutrition, development》2004,44(4):321-332
An experiment was performed to study the effect of the feeding program and age at first mating on body growth, feed intake, reproductive performance, and culling of rabbit does over three parities, using 155 does of a strain of New Zealand white rabbits. Three treatments were applied. Ad libitum feeding until first insemination at 14.5 wk (AL-14.5) or 17.5 wk of age (AL-17.5), and restrictive feeding from five wk of age until first insemination at 17.5 wk of age (R-17.5). At first insemination, the BW of AL-14.5 and R-17.5 was similar (3 907 vs. 3 791 +/- 46 g, respectively), whereas AL-17.5 does were heavier (4 390 +/- 46 g, P < 0.001). During reproduction, performance of AL-17.5 was not improved compared to AL-14.5 and R-17.5 does. Al-17.5 does showed a lower feed intake during the first gestation (-25%) and first parity (-10%) than R- 17.5, resulting in weight loss (-6%) during the first gestation and decreased litter weights (-19%) and litter growth (-14%) in the first parity. Extended first mating by three wk (17.5 vs. 14.5 wk) but similar BW at first mating did not affect feed intake and BW development during the first three parities. However, the number of live born kits and weight at first kindling, and litter growth in the first parity were improved in R-17.5 (+23%, +18%, and +14%, respectively). Reproductive performance can be improved by restricted feeding during rearing and extended first insemination to 17.5 wk of age. However, the culling rate was not affected by the rearing strategy. 相似文献
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Zohar R Zhu B Liu P Sodek J McCulloch CA 《American journal of physiology. Heart and circulatory physiology》2004,287(4):H1730-H1739
Reperfusion-induced oxidative injury to the myocardium promotes activation and proliferation of cardiac fibroblasts and repair by scar formation. Osteopontin (OPN) is a proinflammatory cytokine that is upregulated after reperfusion. To determine whether OPN enhances fibroblast survival after exposure to oxidants, cardiac fibroblasts from wild-type (WT) or OPN-null (OPN(-/-)) mice were treated in vitro with H(2)O(2) to model reperfusion injury. Within 1 h, membrane permeability to propidium iodide (PI) was increased from 5 to 60% in OPN(-/-) cells but was increased to only 20% in WT cells. In contrast, after 1-8 h of treatment with H(2)O(2), the percent of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-stained cells was more than twofold higher in WT than OPN(-/-) cells. Electron microscopy of WT cells treated with H(2)O(2) showed chromatin condensation, nuclear fragmentation, and cytoplasmic and nuclear shrinkage, which are consistent with apoptosis. In contrast, H(2)O(2)-treated OPN(-/-) cardiac fibroblasts exhibited cell and nuclear swelling and membrane disruption that are indicative of cell necrosis. Treatment of OPN(-/-) and WT cells with a cell-permeable caspase-3 inhibitor reduced the percentage of TUNEL staining by more than fourfold in WT cells but decreased staining in OPN(-/-) cells by approximately 30%. Although the percentage of PI-permeable WT cells was reduced threefold, the percent of PI-permeable OPN(-/-) cells was not altered. Restoration of OPN expression in OPN(-/-) fibroblasts reduced the percentage of PI-permeable cells but not TUNEL staining after H(2)O(2) treatment. Thus H(2)O(2)-induced cell death in OPN-deficient cardiac fibroblasts is mediated by a caspase-3-independent, necrotic pathway. We suggest that the increased expression of OPN in the myocardium after reperfusion may promote fibrosis by protecting cardiac fibroblasts from cell death. 相似文献
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Weiss EI Kozlovsky A Steinberg D Lev-Dor R Bar Ness Greenstein R Feldman M Sharon N Ofek I 《FEMS microbiology letters》2004,232(1):89-92
Previous investigations showed that a high molecular mass, non-dialyzable material (NDM) from cranberries inhibits the adhesion of a number of bacterial species and prevents the co-aggregation of many oral bacterial pairs. In the present study we determined the effect of mouthwash supplemented with NDM on oral hygiene. Following 6 weeks of daily usage of cranberry-containing mouthwash by an experimental group (n = 29), we found that salivary mutans streptococci count as well as the total bacterial count were reduced significantly (ANOVA, P < 0.01) compared with those of the control (n = 30) using placebo mouthwash. No change in the plaque and gingival indices was observed. In vitro, the cranberry constituent inhibited the adhesion of Streptococcus sobrinus to saliva-coated hydroxyapatite. The data suggest that the ability to reduce mutans streptococci counts in vivo is due to the anti-adhesion activity of the cranberry constituent. 相似文献
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