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排序方式: 共有71条查询结果,搜索用时 15 毫秒
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Ryan D. Mohan George Dialynas Vikki M. Weake Jianqi Liu Skylar Martin-Brown Laurence Florens Michael P. Washburn Jerry L. Workman Susan M. Abmayr 《Genes & development》2014,28(3):259-272
The Spt–Ada–Gcn5–acetyltransferase (SAGA) chromatin-modifying complex possesses acetyltransferase and deubiquitinase activities. Within this modular complex, Ataxin-7 anchors the deubiquitinase activity to the larger complex. Here we identified and characterized Drosophila Ataxin-7 and found that reduction of Ataxin-7 protein results in loss of components from the SAGA complex. In contrast to yeast, where loss of Ataxin-7 inactivates the deubiquitinase and results in increased H2B ubiquitination, loss of Ataxin-7 results in decreased H2B ubiquitination and H3K9 acetylation without affecting other histone marks. Interestingly, the effect on ubiquitination was conserved in human cells, suggesting a novel mechanism regulating histone deubiquitination in higher organisms. Consistent with this mechanism in vivo, we found that a recombinant deubiquitinase module is active in the absence of Ataxin-7 in vitro. When we examined the consequences of reduced Ataxin-7 in vivo, we found that flies exhibited pronounced neural and retinal degeneration, impaired movement, and early lethality. 相似文献
3.
Dudani R Giordano L Sultania P Jha K Florens A Joseph T 《American journal of perinatology》2008,25(4):229-231
Juvenile granulosa cell tumor (JGCT) of testis is extremely rare in childhood. It is considered a benign entity because metastasis has never been reported. Testicular-sparing surgery is the recommended treatment. We reported this case in a newborn who presented with unilateral scrotal swelling. Histopathology and immunohistochemistry confirmed JGCT. Follow-up at 6 months after surgery did not show any recurrence. Even though JGCT is very rare in childhood, it is one of the important differentials of newborn scrotal mass. 相似文献
4.
Phillips GR Anderson TR Florens L Gudas C Magda G Yates JR Colman DR 《Journal of neuroscience research》2004,78(1):38-48
CNS synapses are complex sites of cell-cell communication. Identification and characterization of the protein components of synapses will lead to a better understanding of the mechanisms of neurotransmission and plasticity. We applied multidimensional protein identification technology (MudPIT) to purified, guanidine-solubilized postsynaptic fractions to identify novel synaptically localized molecules. We identified several actin-associated proteins known to regulate actin polymerization and control cell motility in nonneural cells that have not previously been associated with CNS synaptic function. One of these is lasp-1, an actin-associated LIM and SH3 domain-containing protein. We show that lasp-1 is strongly expressed by CNS neurons and is concentrated at synaptic sites. Overall, the preponderance of actin-associated proteins in postsynaptic density fractions, and specifically those involved in actin reorganization, suggests that there are many modes by which the state of synaptic F-actin polymerization and, hence, synaptic physiology are affected. 相似文献
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Skaar JR Florens L Tsutsumi T Arai T Tron A Swanson SK Washburn MP DeCaprio JA 《Cancer research》2007,67(5):2006-2014
CUL7 and the p53-associated, PARkin-like cytoplasmic protein (PARC) were previously reported to form homodimers and heterodimers, the first demonstration of cullin dimerization. Although a CUL7-based SKP1/CUL1/F-box (SCF)-like complex has been observed, little is known about the existence of a PARC-based SCF-like complex and how PARC interacts with CUL7-based complexes. To further characterize PARC-containing complexes, we examined the ability of PARC to form an SCF-like complex. PARC binds RBX1 and is covalently modified by NEDD8, defining PARC as a true cullin. However, PARC fails to bind SKP1 or F-box proteins, including the CUL7-associated FBXW8. To examine the assembly of PARC- and CUL7-containing complexes, tandem affinity purification followed by multidimensional protein identification technology were used. Multidimensional protein identification technology analysis revealed that the CUL7 interaction with FBXW8 was mutually exclusive of CUL7 binding to PARC or p53. Notably, although heterodimers of CUL7 and PARC bind p53, p53 is not required for the dimerization of CUL7 and PARC. The observed physical separation of FBXW8 and PARC is supported functionally by the generation of Parc-/-, Fbxw8-/- mice, which do not show exacerbation of the Fbxw8-/- phenotype. Finally, all of the PARC and CUL7 subcomplexes examined exhibit E3 ubiquitin ligase activity in vitro. Together, these findings indicate that the intricate assembly of PARC- and CUL7-containing complexes is highly regulated, and multiple subcomplexes may exhibit ubiquitin ligase activity. 相似文献
7.
Versteegh FG Buma SA Costin G de Jong WC Hennekam RC;EvC Working Party 《American journal of medical genetics. Part A》2007,(18):2113-2121
Little is known on growth, growth hormone (GH) levels and GH treatment in patients with Ellis-van Creveld syndrome (EvC). The aim of the present study was to assess growth, growth hormone status and the possible effectiveness of GH treatment in literature and in a small series of EvC patients. A review of literature indicated retarded growth for most EvC patients (-2 to -4.5 SDS) and minimal data on GH levels or treatment which did not allow any conclusion. We studied eight EvC patients, seven of whom were treated with GH. Four were GH deficient (GHD) and four were GH sufficient. In all patients treated with GH, first year growth velocity increased. In three of the four GHD and in one GH-sufficient patient a gain in height SDS was noted. In the present small EvC series GHD occurred more often than expected. Patient acquisition through the Growth Hormone Database will have caused a significant bias, but the present results indicate that GH treatment may improve growth in at least some patients with EvC. Therefore we conclude that EvC patients may benefit from being tested for GHD and, if indicated, treated. In addition a prospective study to evaluate GH status and linear growth in patients with EvC as well as the potential effectiveness of GH treatment is warranted. 相似文献
8.
Polderman FN Cohen J Blom NA Delhaas T Helbing WA Lam J Sobotka-Plojhar MA Temmerman AM Sreeram N 《International journal of cardiology》2004,95(2-3):171-176
BACKGROUND: It is known that children with previously diagnosed heart defects die suddenly. The causes of death are often unknown. OBJECTIVE: The aim of the study was to identify all infants and children within the Netherlands with previously diagnosed heart disease who had a sudden unexpected death (SUD), and to identify the possible cause of death. DESIGN: Retrospective, cross-sectional study. PATIENTS AND SETTING: All children (<19 years) with a previously diagnosed heart defect and SUD between January 1990 and June 2001 in seven out of eight tertiary centres in the Netherlands were identified using the hospital databases. We excluded patients receiving compassionate care. Diagnoses, clinical status and circumstances of death were sought from case notes and post mortem reports. Deaths were classified as of cardiac or non-cardiac origin. RESULTS: We identified 150 cases of SUD (89 male) at a median age of 2.3 years (range 18 days-18.9 years); 49/150 patients (33%) were =1 year. Diagnostic categories included left to right shunts (N=34, 14 =1 year), cyanotic lesions (N=38, 13 <==1 yar), cardiomyopathy (N=11, 2 =1 year), univentricular heart (N=24, 10 =1 year), obstructive lesions (N=11, 3 =1 year), arrhythmia (N=8, 0 =1 year), and miscellaneous defects (N=18, 5 =1 year). 108/150 patients (72%) had been operated of whom 61 (57%) had corrective surgery. Of the infants with SUD, 32/49 (65%) had undergone surgery (11 corrective); 76/101 older children had undergone previous surgery (50 corrective). 114/150 children (76%) died of a cardiac cause. Causes of death were arryhythmia (59), heart failure (25), shunt occlusion (10), pulmonary hypertensive crisis (8) and acute myocardial infarction (4). 30/49 infants (61%) died of a cardiac cause; causes of death included arrythmia (10), heart failure (8), shunt occlusion (7), acute myocardial infarction (2). CONCLUSIONS: SUD in children with heart defects were predominantly of cardiac origin. Pumpfailure and arrhythmias were the terminal events in a significant number of patients in the entire population. 相似文献
9.
Identification of Plasmodium falciparum antigens by antigenic analysis of genomic and proteomic data
Doolan DL Southwood S Freilich DA Sidney J Graber NL Shatney L Bebris L Florens L Dobano C Witney AA Appella E Hoffman SL Yates JR Carucci DJ Sette A 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(17):9952-9957
The recent explosion in genomic sequencing has made available a wealth of data that can now be analyzed to identify protein antigens, potential targets for vaccine development. Here we present, in the context of Plasmodium falciparum, a strategy that rapidly identifies target antigens from large and complex genomes. Sixteen antigenic proteins recognized by volunteers immunized with radiation-attenuated P. falciparum sporozoites, but not by mock immunized controls, were identified. Several of these were more antigenic than previously identified and well characterized P. falciparum-derived protein antigens. The data suggest that immune responses to Plasmodium are dispersed on a relatively large number of parasite antigens. These studies have implications for our understanding of immunodominance and breadth of responses to complex pathogens. 相似文献
10.
Amanda M. Bonner Stacie E. Hughes Jennifer A. Chisholm S. Kendall Smith Brian D. Slaughter Jay R. Unruh Kimberly A. Collins Jennifer M. Friederichs Laurence Florens Selene K. Swanson Marissa C. Pelot Danny E. Miller Michael P. Washburn Sue L. Jaspersen R. Scott Hawley 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(13):E1222-E1231
Drosophila melanogaster Polo kinase physically interacts with, and is repressed by, the Matrimony (Mtrm) protein during oogenesis. Females heterozygous for a deletion of the mtrm gene display defects in chromosome segregation at meiosis I. However, a complete absence of Mtrm results in both meiotic catastrophe and female sterility. We show that three phosphorylated residues in an N-terminal region in Mtrm are required for Mtrm::Polo binding. However, this binding is noncanonical; it does not require either a complete S-pS/pT-P motif in Mtrm or key residues in the Polo-box domain of Polo that allow Polo to bind phosphorylated substrates. By using fluorescence cross-correlation spectroscopy to characterize the Mtrm::Polo interaction in vivo, we show that a sterile α-motif (SAM) domain located at the C terminus of Mtrm increases the stability of Mtrm::Polo binding. Although Mtrm’s C-terminal SAM domain is not required to rescue the chromosome segregation defects observed in mtrm/+ females, it is essential to prevent both meiotic catastrophe and the female sterility observed in mtrm/mtrm females. We propose that Polo’s interaction with the cluster of phosphorylated residues alone is sufficient to rescue the meiosis I defect. However, the strengthening of Mtrm::Polo binding mediated by the SAM domain is necessary to prevent meiotic catastrophe and ensure female fertility. Characterization of the Mtrm::Polo interaction, as well as that of other Polo regulators, may assist in the design of a new class of Polo inhibitors to be used as targeted anticancer therapeutic agents.Successful cell division requires the careful coordination of multiple processes, such as DNA replication, nuclear envelope breakdown (NEB), alignment and segregation of chromosomes on the spindle, and finally, cytokinesis. Temporal and spatial control of these events is partially regulated by Polo-like kinases, hereafter referred to as Polo, which are conserved from budding yeast (Cdc5) to humans (Plk1) (1–4). Polo is comprised of two functional domains—a canonical N-terminal serine/threonine kinase domain and a unique C-terminal Polo-box domain (PBD)—that are separated by a flexible linker region. The noncatalytic PBD consists of two Polo boxes, PB1 and PB2, which function as a single protein-binding unit.Studies in several organisms have identified a number of mutations within the PBD that abrogate its ability to selectively bind phosphorylated proteins containing the core consensus motif S-pS/pT-P/X (5–8). The classic “pincer mutant,” which fails to bind the core consensus motif S-pS/pT-P/X of Polo targets, was first identified as an H538A, K540M double-mutant residing within PB2 of human Plk1 (5, 6). (The equivalent mutations within the highly conserved PB2 of Drosophila Polo are H518A and K520M.) One example of this type of binding is the interaction between Plk1 and Bub1, a spindle checkpoint protein, in mitotic HeLa cells. This interaction requires the phosphorylation of Bub1 at a threonine within a conserved S-pT-P PBD binding motif and is critical for the proper localization of endogenous Plk1 to kinetochores during mitosis. The Polo::Bub1 interaction is also dependent on the PBD, as the Plk1 H538A, K540M pincer mutant is unable to coimmunoprecipitate (co-IP) with the Bub1 protein (8).However, it is becoming increasingly clear that Polo is also capable of interacting with regulatory proteins via noncanonical mechanisms (7). For example, in Drosophila S2 cells, Polo has been shown to robustly interact with the microtubule-associated protein Map205 during interphase of the cell cycle (9). Although a functional PBD and some structural elements of the Polo kinase domain, as well as a 162-aa region in Map205, are required for this interaction, it occurs by a phospho-independent mechanism (9). Although other examples of noncanonical Polo binding will be discussed below (Discussion), we focus here on the interaction between Drosophila Polo and its regulator Matrimony (Mtrm).Although the Mtrm protein was first shown to be a Polo binding protein by a global yeast two-hybrid (Y2H) interaction screen (10), the mtrm gene was identified in a genetic screen for genes that were haplo-insufficient with respect to the proper segregation of achiasmate homologs at the first meiotic division (11). Loss-of-function alleles of mtrm cause three distinct phenotypes: (i) high levels of achiasmate chromosome missegregation in mtrm/+ females, (ii) precocious NEB in mtrm/+ and mtrm/mtrm females, and (iii) sterility in females with a mtrm-null mutant background (12). The interaction between Mtrm and Polo was demonstrated genetically by the finding that reducing the dose of the polo+ gene to one copy fully suppressed the chromosome segregation defect seen in mtrm/+ females, while increasing the dose of the polo+ gene to three copies in females with two functional copies of mtrm+ induced defects in chromosome segregation (12). Xiang et al. (12) confirmed the physical interaction of Mtrm and Polo observed in Y2H studies with Drosophila oocytes by co-IP and proteomic analysis (12). These observations support a model in which Mtrm binding serves to inhibit the activity of Polo, and lend evidence to the idea that unbound Polo is deleterious to proper chromosome segregation during meiosis I.Although it remains to be shown biochemically, multiple lines of genetic evidence strongly suggest that Mtrm acts by inhibiting the activity of Polo kinase, and that Polo is likely to be the only target of Mtrm. First, as noted above, mutants in polo dominantly suppress the meiotic defects seen in mtrm/+ heterozygotes (12). Second, others have demonstrated a genetic interaction of Mtrm with other regulators of Polo, most notably, Scant (a dominant allele of greatwall) and endos (13, 14). Third, Von Stetina et al. (14) demonstrated that reducing polo+ dosage suppressed the decreased fertility observed in mtrm endos double heterozygotes. The authors also showed that increasing the dosage of polo+ to three copies resulted in almost complete sterility of mtrm heterozygous females (14). Fourth, in the proteomic studies performed by Xiang et al. (12) in which Mtrm was used as the bait protein, Polo was the only consistent high-affinity interactor.In Xiang et al. (12), immunofluorescence studies suggested that the amount of Mtrm was greatly decreased at the end of stage 12, coincident with NEB (12, 15). However, Von Stetina et al. (14) clearly showed by Western blot analysis that Mtrm levels substantially increase in stages 13 and 14. Indeed, we show below that the concentration of both Mtrm and Polo increases by approximately fivefold during the transition from stage 13 to stage 14. In this article we characterize both the role of Mtrm as a regulator of Polo at stages 13 and 14 and the nature of the physical Mtrm::Polo interaction.Although Xiang et al. (12) initially suggested that Mtrm and Polo interacted via a canonical interaction of the PBD of Polo with the S-pT-P motif of Mtrm, we use three techniques [co-IP from Drosophila ovaries, Y2H analysis, and fluorescence cross-correlation spectroscopy (FCCS) studies in living stage 13 and 14 oocytes] to demonstrate that the interaction of Mtrm and Polo is actually mediated by at least two highly conserved regions in Mtrm, an 18-aa N-terminal region that includes the S-pT40-P motif and a 61-aa C-terminal sterile α-motif (SAM) domain (Fig. 1A). The Mtrm::Polo interaction does not require the serine at the −1 position of the S-pT40-P motif, demonstrating that this interaction does not explicitly follow the canonical mechanism previously described (6).Open in a separate windowFig. 1.The binding of Mtrm to Polo is noncanonical. Residues in two distinct regions of Mtrm are required for Mtrm to fully bind Polo (A–C). The pincer residues in the PBD of Polo, which are generally essential for Polo to bind its substrates, are not required for full Mtrm::Polo binding. (D–F). (A) A schematic representation of the Mtrm protein depicting the two regions of conservation analyzed: the N-terminal region shown in yellow and the SAM domain shown in blue. (B) Coimmunoprecipitation was performed on FLAG-tagged overexpression transgenic lines expressing either full-length or a mutated form of the Mtrm protein. Both truncations, MtrmNterm-deletion (lane 3) and MtrmSAM-deletion (lane 4) were unable to bind Polo. The Mtrm::Polo interaction was also disrupted for MtrmT40A (lane 6), MtrmS48A (lane 7), and MtrmS52A (lane 8); MtrmS39A (lane 5) and MtrmS137A (lane 9) showed Mtrm::Polo binding similar to MtrmFL (lane 2). Although MtrmS52A levels were reduced in this co-IP it showed higher expression in replicate experiments, and Polo binding was still decreased. Full genotypes of the transgenic lines were y w;transgene/+;nanosGAL4:VP16/+ and no-construct flies were y w;spapol. (C) FCCS was performed on mCherry-tagged Mtrm proteins with GFP-tagged Polo protein. Tagged constructs were expressed with their genomic promoters and flies were y w/w;mCherry-mtrm/GFP-polo. (D) A schematic representation of the Polo kinase protein depicting the kinase domain in green and the two PBDs in yellow and blue. (E) Co-IP was performed on GFP-tagged transgenic lines expressing either full-length or a mutant form of the Polo protein. The classic pincer mutant, poloH518A
K520M was able to bind Mtrm at levels comparable to polowt. Full genotypes of the transgenic lines were w;GFP-polo, and no-construct flies were y w;spapol. (F) FCCS was performed on mCherry-tagged Mtrm protein with GFP-tagged Polo proteins. Flies were y w/w;mCherry-mtrm/GFP-polo. Negative cross-correlation may be observed when diffusion of two species is not random, but some factor actively causes them to be segregated in space or time. However, in this case, cross-correlation values in select cases appear negative because of uncertainties in the measurement, as none of the negative cross-correlation values are statistically indistinguishable from the null hypothesis.Finally, we demonstrate that Polo and Mtrm use a noncanonical mechanism of interaction with regard to the PBD. Mutational ablation of the classic pincer residues within PB2 does not prevent Polo from binding Mtrm in co-IP experiments. Moreover, FCCS studies show that the Polo pincer mutant retains a strong ability to bind Mtrm in vivo, providing further evidence for noncanonical binding. We propose a model in which Polo’s interaction with the N-terminal cluster of three phosphorylatable Mtrm residues alone is sufficient to rescue the meiosis I defect, but strengthening of Mtrm::Polo binding, which is mediated by the SAM domain, is necessary to prevent meiotic catastrophe and ensure female fertility. 相似文献