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Amino-terminal protein-protein interaction motif (POZ-domain) is responsible for activities of the promyelocytic leukemia zinc finger-retinoic acid receptor-alpha fusion protein. 总被引:16,自引:1,他引:16 下载免费PDF全文
S Dong J Zhu A Reid P Strutt F Guidez H J Zhong Z Y Wang J Licht S Waxman C Chomienne et al. 《Proceedings of the National Academy of Sciences of the United States of America》1996,93(8):3624-3629
Promyelocytic leukemia zinc finger-retinoic acid receptor a (PLZF-RARalpha), a fusion receptor generated as a result of a variant t(11;17) chromosomal translocation that occurs in a small subset of acute promyelocytic leukemia (APL) patients, has been shown to display a dominant-negative effect against the wild-type RARalpha/retinoid X receptor alpha (RXRalpha). We now show that its N-terminal region (called the POZ-domain), which mediates protein-protein interaction as well as specific nuclear localization of the wild-type PLZF and chimeric PLZF-RARalpha proteins, is primarily responsible for this activity. To further investigate the mechanisms of PLZF-RARalpha action, we have also studied its ligand-receptor, protein-protein, and protein-DNA interaction properties and compared them with those of the promyelocytic leukemia gene (PML)-RARalpha, which is expressed in the majority of APLs as a result of t(15;17) translocation. PLZF-RARalpha and PML-RARalpha have essentially the same ligand-binding affinities and can bind in vitro to retinoic acid response elements (RAREs) as homodimers or heterodimers with RXRalpha. PLZF-RARalpha homodimerization and heterodimerization with RXRalpha were primarily mediated by the POZ-domain and RARalpha sequence, respectively. Despite having identical RARalpha sequences, PLZF-RARalpha and PML-RARalpha homodimers recognized with different affinities distinct RAREs. Furthermore, PLZF-RARalpha could heterodimerize in vitro with the wild-type PLZF, suggesting that it may play a role in leukemogenesis by antagonizing actions of not only the retinoid receptors but also the wild-type PLZF and possibly other POZ-domain-containing regulators. These different protein-protein interactions and the target gene specificities of PLZF-RARalpha and PML-RARalpha may underlie, at least in part, the apparent resistance of APL with t(11;17) to differentiation effects of all-trans-retinoic acid. 相似文献
34.
Jane Topolovec-Vranic Marlene Santos Andrew J Baker Orla M Smith Karen EA Burns 《Canadian respiratory journal》2014,21(5):293-296
INTRODUCTION:
Alterations from first-party and surrogate decision-maker consent can enhance the feasibility of research involving critically ill patients.OBJECTIVE:
To describe the use of a deferred-consent model to enable participation of critically ill patients in a minimal-risk biomarker study.METHODS:
A prospective observational study was conducted in which serum biomarker samples were collected three times daily over the first 14 days following aneurysmal subarachnoid hemorrhage. Sample collection was initiated on intensive care unit admission and consent was obtained when research personnel could approach the patient or the patient’s surrogate decision maker.RESULTS:
Twenty-seven patients were eligible for the study, of whom only five were capable of providing informed consent. Full consent was obtained for 21 (78%) patients through self- (n=4) and surrogate (n=17) consent. Partial consent or refusal (only permitting the collection of blood samples as a part of routine care or use of data) occurred in three patients. Among the 22 consents sought from surrogates, three (11%) refused participation. The refusals included the sickest patients in the cohort. Once consent was provided, no patient or surrogate withdrew consent before study completion.DISCUSSION:
Use of a deferred consent model enabled participation of critically ill patients in a minimal-risk biomarker study with no withdrawals.CONCLUSIONS:
Further research and enhanced awareness of the potential utility of hybrid models, including deferred consent in addition to patient or surrogate consent, in the conduct of low-risk and minimally interventional time-sensitive studies of critically ill patients are required. 相似文献35.
36.
Sprouty proteins are established modifiers of receptor tyrosine kinase (RTK) signaling and play important roles in vasculogenesis, bone morphogenesis, and renal uteric branching. Little is understood, however, concerning possible roles for these molecular adaptors during hematopoiesis. Within erythroid lineage, Spry1 was observed to be selectively and highly expressed at CFU-e to erythroblast stages. In analyses of possible functional roles, an Mx1-Cre approach was applied to conditionally delete Spry1. At steady state, Spry1 deletion selectively perturbed erythroid development and led to reticulocytosis plus heightened splenic erythropoiesis. When challenged by hemolysis, Spry1-null mice exhibited worsened anemia and delayed recovery. During short-term marrow transplantation, Spry1-null donor marrow also failed to efficiently rescue the erythron. In each anemia model, however, hyperexpansion of erythroid progenitors was observed. Spry function depends on phosphorylation of a conserved N-terminal PY motif. Through an LC-MS/MS approach, Spry1 was discovered to be regulated via the erythropoietin receptor (EPOR), with marked EPO-induced Spry1-PY53 phosphorylation observed. When EPOR signaling pathways were analyzed within Spry1-deficient erythroid progenitors, hyperactivation of not only Erk1,2 but also Jak2 was observed. Studies implicate Spry1 as a novel regulator of erythropoiesis during anemia, transducer of EPOR signals, and candidate suppressor of Jak2 activity. 相似文献
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David K. Hooper Jason C. Williams Adam C. Carle Sandra Amaral Deepa H. Chand Maria E. Ferris Hiren P. Patel Christoph Licht Gina-Marie Barletta Veronica Zitterman Mark Mitsnefes Uptal D. Patel 《Pediatric nephrology (Berlin, Germany)》2013,28(6):939-949
Background
Cardiovascular disease is the leading cause of increased mortality for adolescents with advanced kidney disease. The quality of preventive cardiovascular care may impact long-term outcomes for these patients.Methods
We reviewed the records of 196 consecutive adolescents from eight centers with pre-dialysis chronic kidney disease, on dialysis or with a kidney transplant, who transferred to adult-focused providers. We compared cardiovascular risk assessment and therapy within and across centers. Predictors of care were assessed using multilevel models.Results
Overall, 58 % (range 44–86 %; p?=?0.08 for variance) of five recommended cardiovascular risk assessments were documented. Recommended therapy for six modifiable cardiovascular risk factors was documented 57 % (26–76 %; p?=?0.09) of the time. Of these patients, 30 % (n?=?59) were reported to go through formal transition which was independently associated with a 21 % increase in composite cardiovascular risk assessment (p?<?0.001). Transfer after 2006 and kidney transplant status were also associated with increased cardiovascular risk assessment (p?<?0.01 and p?=?0.045, respectively).Conclusions
Adolescents with kidney disease receive suboptimal preventive cardiovascular care, that may contribute to their high risk of future cardiovascular mortality. A great opportunity exists to improve outcomes for children with kidney disease by improving the reliability of preventive care that may include formal transition programs. 相似文献39.
Badria Al-Ghaithi Rahul Chanchlani Magdalena Riedl Paul Thorner Christoph Licht 《Pediatric nephrology (Berlin, Germany)》2016,31(11):2079-2086
Background
Post-infectious glomerulonephritis (PIGN) usually follows a benign course, but few children have an atypical, severe presentation, and these exceptional cases have been linked to the dysregulation of the complement alternative pathway (CAP). There is a considerable overlap in the histopathological features of PIGN and C3 glomerulopathy (C3G), which is also associated with CAP dysregulation but has a poorer outcome. We hypothesized that PIGN and C3G define a disease spectrum, and that in the past there may be some children with C3G who were misclassified with PIGN before C3G was described as a separate disease entity.Methods
Children with PIGN (n?=?33) diagnosed between 1985 and 2010 who underwent a renal biopsy due to their unusual course were reviewed and of them, 8 were reclassified into C3G based on the current classification criteria. Outcome was based on the degree of proteinuria, C3 level, and renal function at follow-up.Results
Sixteen (72.7%) children with typical PIGN recovered completely as compared to only 2 (25%) with C3G. Of note, children with “typical” PIGN had a more severe disease course at onset; however, the outcome at last follow up was favorable.Conclusions
Our results support the hypothesis that PIGN and C3G form a disease spectrum and have different long-term clinical implications and management strategies.40.
Chantal Loirat Fadi Fakhouri Gema Ariceta Nesrin Besbas Martin Bitzan Anna Bjerre Rosanna Coppo Francesco Emma Sally Johnson Diana Karpman Daniel Landau Craig B Langman Anne-Laure Lapeyraque Christoph Licht Carla Nester Carmine Pecoraro Magdalena Riedl Nicole C. A. J. van de Kar Johan Van de Walle Marina Vivarelli Véronique Frémeaux-Bacchi for HUS International 《Pediatric nephrology (Berlin, Germany)》2016,31(1):15-39