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101.
Regulation of p53 activity through lysine methylation 总被引:1,自引:0,他引:1
Chuikov S Kurash JK Wilson JR Xiao B Justin N Ivanov GS McKinney K Tempst P Prives C Gamblin SJ Barlev NA Reinberg D 《Nature》2004,432(7015):353-360
p53 is a tumour suppressor that regulates the cellular response to genotoxic stresses. p53 is a short-lived protein and its activity is regulated mostly by stabilization via different post-translational modifications. Here we report a novel mechanism of p53 regulation through lysine methylation by Set9 methyltransferase. Set9 specifically methylates p53 at one residue within the carboxyl-terminus regulatory region. Methylated p53 is restricted to the nucleus and the modification positively affects its stability. Set9 regulates the expression of p53 target genes in a manner dependent on the p53-methylation site. The crystal structure of a ternary complex of Set9 with a p53 peptide and the cofactor product S-adenosyl-l-homocysteine (AdoHcy) provides the molecular basis for recognition of p53 by this lysine methyltransferase. 相似文献
102.
103.
Sohn RA Willis C Humphris S Shank TM Singh H Edmonds HN Kunz C Hedman U Helmke E Jakuba M Liljebladh B Linder J Murphy C Nakamura K Sato T Schlindwein V Stranne C Tausenfreund M Upchurch L Winsor P Jakobsson M Soule A 《Nature》2008,453(7199):1236-1238
Roughly 60% of the Earth's outer surface is composed of oceanic crust formed by volcanic processes at mid-ocean ridges. Although only a small fraction of this vast volcanic terrain has been visually surveyed or sampled, the available evidence suggests that explosive eruptions are rare on mid-ocean ridges, particularly at depths below the critical point for seawater (3,000 m). A pyroclastic deposit has never been observed on the sea floor below 3,000 m, presumably because the volatile content of mid-ocean-ridge basalts is generally too low to produce the gas fractions required for fragmenting a magma at such high hydrostatic pressure. We employed new deep submergence technologies during an International Polar Year expedition to the Gakkel ridge in the Arctic Basin at 85 degrees E, to acquire photographic and video images of 'zero-age' volcanic terrain on this remote, ice-covered ridge. Here we present images revealing that the axial valley at 4,000 m water depth is blanketed with unconsolidated pyroclastic deposits, including bubble wall fragments (limu o Pele), covering a large (>10 km(2)) area. At least 13.5 wt% CO(2) is necessary to fragment magma at these depths, which is about tenfold the highest values previously measured in a mid-ocean-ridge basalt. These observations raise important questions about the accumulation and discharge of magmatic volatiles at ultraslow spreading rates on the Gakkel ridge and demonstrate that large-scale pyroclastic activity is possible along even the deepest portions of the global mid-ocean ridge volcanic system. 相似文献
104.
Julia Scharnert Lilo Greune Dagmar Zeuschner Marie-Luise Lubos M. Alexander Schmidt Christian Rüter 《Cellular and molecular life sciences : CMLS》2013,70(24):4809-4823
Extracellular Gram-negative pathogenic bacteria target essential cytoplasmic processes of eukaryotic cells by using effector protein delivery systems such as the type III secretion system (T3SS). These secretion systems directly inject effector proteins into the host cell cytoplasm. Among the T3SS-dependent Yop proteins of pathogenic Yersinia, the function of the effector protein YopM remains enigmatic. In a recent study, we demonstrated that recombinant YopM from Yersinia enterocolitica enters host cells autonomously without the presence of bacteria and thus identified YopM as a novel bacterial cell-penetrating protein. Following entry YopM down-regulates expression of pro-inflammatory cytokines such as tumor necrosis factor α. These properties earmark YopM for further development as a novel anti-inflammatory therapeutic. To elucidate the uptake and intracellular targeting mechanisms of this bacterial cell-penetrating protein, we analyzed possible routes of internalization employing ultra-cryo electron microscopy. Our results reveal that under physiological conditions, YopM enters cells predominantly by exploiting endocytic pathways. Interestingly, YopM was detected free in the cytosol and inside the nucleus. We could not observe any colocalization of YopM with secretory membranes, which excludes retrograde transport as the mechanism for cytosolic release. However, our findings indicate that direct membrane penetration and/or an endosomal escape of YopM contribute to the cytosolic and nuclear localization of the protein. Surprisingly, even when endocytosis is blocked, YopM was found to be associated with endosomes. This suggests an intracellular endosome-associated transport of YopM. 相似文献
105.
Melinda Halasz Beata Polgar Gergely Berta Livia Czimbalek Julia Szekeres-Bartho 《Cellular and molecular life sciences : CMLS》2013,70(23):4617-4630
Invasiveness is a common feature of trophoblast and tumors; however, while tumor invasion is uncontrolled, trophoblast invasion is strictly regulated. Both trophoblast and tumor cells express high levels of the immunomodulatory progesterone-induced blocking factor (PIBF), therefore, we aimed to test the possibility that PIBF might be involved in invasion. To this aim, we used PIBF-silenced or PIBF-treated trophoblast (HTR8/Svneo, and primary trophoblast) and tumor (HT-1080, A549, HCT116, PC3) cell lines. Silencing of PIBF increased invasiveness as well as MMP-2,-9 secretion of HTR8/SVneo, and decreased those of HT-1080 cells. PIBF induced immediate STAT6 activation in both cell lines. Silencing of IL-4Rα abrogated all the above effects of PIBF, suggesting that invasion-related signaling by PIBF is initiated through the IL-4Rα/PIBF-receptor complex. In HTR-8/SVneo, PIBF induced fast, but transient Akt and ERK phosphorylation, whereas in tumor cells, PIBF triggered sustained Akt, ERK, and late STAT3 activation. The late signaling events might be due to indirect action of PIBF. PIBF induced the expression of EGF and HB-EGF in HT-1080 cells. The STAT3-activating effect of PIBF was reduced in HB-EGF-deficient HT-1080 cells, suggesting that PIBF-induced HB-EGF contributes to late STAT3 activation. PIBF binds to the promoters of IL-6, EGF, and HB-EGF; however, the protein profile of the protein/DNA complex is different in the two cell lines. We conclude that in tumor cells, PIBF induces proteins, which activate invasion signaling, while—based on our previous data—PIBF might control trophoblast invasion by suppressing proinvasive genes. 相似文献
106.
Meimaridou E Kowalczyk J Guasti L Hughes CR Wagner F Frommolt P Nürnberg P Mann NP Banerjee R Saka HN Chapple JP King PJ Clark AJ Metherell LA 《Nature genetics》2012,44(7):740-742
Using targeted exome sequencing, we identified mutations in NNT, an antioxidant defense gene, in individuals with familial glucocorticoid deficiency. In mice with Nnt loss, higher levels of adrenocortical cell apoptosis and impaired glucocorticoid production were observed. NNT knockdown in a human adrenocortical cell line resulted in impaired redox potential and increased reactive oxygen species (ROS) levels. Our results suggest that NNT may have a role in ROS detoxification in human adrenal glands. 相似文献
107.
108.
Exogenous double-stranded RNA (dsRNA) has been shown to exert homology-dependent effects at the level of both target mRNA stability and chromatin structure. Using C. elegans undergoing RNAi as an animal model, we have investigated the generality, scope and longevity of dsRNA-targeted chromatin effects and their dependence on components of the RNAi machinery. Using high-resolution genome-wide chromatin profiling, we found that a diverse set of genes can be induced to acquire locus-specific enrichment of histone H3 lysine 9 trimethylation (H3K9me3), with modification footprints extending several kilobases from the site of dsRNA homology and with locus specificity sufficient to distinguish the targeted locus from the other 20,000 genes in the C. elegans genome. Genetic analysis of the response indicated that factors responsible for secondary siRNA production during RNAi were required for effective targeting of chromatin. Temporal analysis revealed that H3K9me3, once triggered by dsRNA, can be maintained in the absence of dsRNA for at least two generations before being lost. These results implicate dsRNA-triggered chromatin modification in C. elegans as a programmable and locus-specific response defining a metastable state that can persist through generational boundaries. 相似文献
109.
Starega-Roslan J Koscianska E Kozlowski P Krzyzosiak WJ 《Cellular and molecular life sciences : CMLS》2011,68(17):2859-2871
110.
Sagane Y Hosp J Zech K Thompson EM 《Cellular and molecular life sciences : CMLS》2011,68(9):1611-1622
Oriented cellulose deposition is critical to plant patterning and models suggest microtubules constrain cellulose synthase
movements through the plasma membrane. Though widespread in plants, urochordates are the only animals that synthesize cellulose.
We characterized the distinctive cellulose microfibril scaffold of the larvacean house and its interaction with house structural
proteins (oikosins). Targeted disruption of cytoskeletal elements, secretory pathways, and plasma membrane organization, suggested
a working model for templating extracellular cellulose microfibrils from animal cells that shows both convergence and differences
to plant models. Specialized cortical F-actin arrays template microfibril orientation and glycosylphosphatidylinositol-anchored
proteins in lipid rafts may act as scaffolding proteins in microfibril elongation. Microtubules deliver and maintain cellulose
synthase complexes to specific cell membrane sites rather than orienting their movement through the membrane. Oikosins are
incorporated into house compartments directly above their corresponding cellular field of expression and interact with the
cellulose scaffold to a variable extent. 相似文献