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941.
Surinder Kaur Barbara Kroczynska Bhumika Sharma Antonella Sassano Ahmet Dirim Arslan Beata Majchrzak-Kita Brady L. Stein Brandon McMahon Jessica K. Altman Bing Su Raffaele A. Calogero Eleanor N. Fish Leonidas C. Platanias 《The Journal of biological chemistry》2014,289(10):6581-6591
We provide evidence that type I IFN-induced STAT activation is diminished in cells with targeted disruption of the Rictor gene, whose protein product is a key element of mTOR complex 2. Our studies show that transient or stable knockdown of Rictor or Sin1 results in defects in activation of elements of the STAT pathway and reduced STAT-DNA binding complexes. This leads to decreased expression of several IFN-inducible genes that mediate important biological functions. Our studies also demonstrate that Rictor and Sin1 play essential roles in the generation of the suppressive effects of IFNα on malignant erythroid precursors from patients with myeloproliferative neoplasms. Altogether, these findings provide evidence for critical functions for Rictor/Sin1 complexes in type I IFN signaling and the generation of type I IFN antineoplastic responses. 相似文献
942.
Giacomo Mangini Francesca Taranto Laura Nunzia Delvecchio Antonella Pasqualone Antonio Blanco 《Molecular breeding : new strategies in plant improvement》2014,34(2):385-392
Polyphenol oxidase (PPO) activity is a major cause of undesirable brown color of semolina. In tetraploid wheat, the Ppo-A1 gene is significantly involved in the phenotypic expression of PPO activity. The main goal of this study was to develop and validate a more efficient marker for Ppo-A1 to facilitate marker-assisted selection for low PPO activity in tetraploid wheat breeding programs. A large tetraploid wheat collection, including durum cultivars, domesticated and wild accessions, was used to evaluate the PPO activity. The heritability values indicated that the phenotypic expression of PPO activity was mainly due to genotypic effect. PPO18, and a new marker named MG18, were used to study the Ppo-A1 allelic variation in a tetraploid wheat collection. PPO18 analysis detected four alleles (Ppo-A1b, Ppo-A1e, Ppo-A1f and Ppo-A1g). The high frequency of Ppo-A1g (no PCR product) detected in the tetraploid wheat collection, led to the development of a new genome-specific Ppo-A1 marker (MG18). MG18 analysis identified the same alleles as PPO18 which were associated with low or high PPO activity. The new MG18 marker was more efficient than PPO18 in detecting the four different alleles of Ppo-A1 in the tetraploid wheat collection. Indeed, the accessions assigned to the Ppo-A1g group, according to PPO18, when tested with MG18, were better classified in the four alleles of the Ppo-A1 gene. The MG18 analysis proved that the PPO18 marker overestimated the number of accessions with Ppo-A1g. Therefore, MG18 can be applied to large-scale marker-assisted selection for PPO activity in durum breeding programs. 相似文献
943.
944.
945.
Antonella Caccamo Smita Majumder Janice J. Deng Yidong Bai Fiona B. Thornton Salvatore Oddo 《The Journal of biological chemistry》2009,284(40):27416-27424
TDP-43 is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. An ∼25-kDa C-terminal fragment of TDP-43 accumulates in affected brain regions, suggesting that it may be involved in the disease pathogenesis. Here, we show that overexpression of the 25-kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous full-length TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular mass neurofilament mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43, whereas inhibition of mTOR, a key protein kinase involved in autophagy regulation, reduces the 25-kDa C-terminal fragment accumulation and restores TDP-43 localization. Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies.TDP-43 (transactive response DNA-binding protein 43) is a conserved and ubiquitously expressed nuclear protein with a theoretical molecular mass of ∼44 kDa. It is encoded by the TARDBP gene on chromosome 1, which is made of six exons that can be alternatively spliced to yield 11 different isoforms, with the mRNA encoding TDP-43 being the major species (1). Functionally, TDP-43 appears to be involved in exon skipping and alternative splicing (2, 3), and it has also been shown to link different types of nuclear bodies (4). Structural studies have confirmed the presence of two RNA recognition motifs (RRM1 and RRM2) and a glycine-rich C-terminal tail, which is thought to mediate protein-protein interaction (5).Recently, TDP-43 has been shown to be the major pathological protein in a wide range of disorders referred to as TDP-43 proteinopathies (6–8). These include frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U),2 motor neuron disease, and amyotrophic lateral sclerosis (ALS). These last two disorders have been directly linked to mutations in TDP-43 (9, 10). In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases (11–14). Sporadic and familial forms of FTLD-U and ALS are characterized by cytoplasmic accumulation of insoluble, hyperphosphorylated, ubiquitinated, and proteolytically cleaved C-terminal fragments in affected brain and spinal cord regions. The cytoplasmic accumulation of TDP-43 is associated with a depletion of nuclear TDP-43 (8, 15–21). These data suggest that some of these TDP-43 proteinopathies may share common mechanisms of pathogenesis.FTLD-U is caused by loss-of-function mutations in the progranulin gene, which lead, by an unknown mechanism, to the accumulation of cytoplasmic TDP-43 inclusions (22, 23). Notably, the TDP-43 inclusions in the ALS and FTLD-U brains are enriched with TDP-43 C-terminal fragments (8, 19). It has been suggested that the C-terminal fragments can be obtained by caspase-dependent cleavage of the full-length protein (24). However, it remains to be established if these fragments play a role in the disease pathogenesis.TDP-43 proteinopathies are characterized by the accumulation of abnormally modified TDP-43, suggesting that dysfunction in the intracellular quality control systems (ubiquitin-proteasome system and the autophagy-lysosome system) may be involved in the disease pathogenesis. The autophagic system is a conserved intracellular system designed for the degradation of long-lived proteins and organelles in lysosomes (25, 26). Three types of autophagy have been described: macroautophagy, microautophagy, and chaperon-mediated autophagy. Whereas macroautophagy and microautophagy involve the “in bulk” degradation of regions of the cytosol (27, 28), chaperon-mediated autophagy is a more selective pathway, and only proteins with a lysosomal targeting sequence are degraded (29). Cumulative evidence has suggested that an age-dependent decrease in the autophagy-lysosome system may account for the accumulation of abnormal proteins during aging (30, 31).Macroautophagy is induced when an isolation membrane is formed surrounding cytosolic components, forming an autophagic vacuole, which will eventually fuse with lysosomes for protein/organelle degradation. Induction of the isolation membrane is negatively regulated by mTOR (mammalian target of rapamycin) (32). It has been shown that increasing autophagy activation by mTOR inhibitors has beneficial effects in neurodegeneration (33–35). 相似文献
946.
947.
Cristiana Almerighi Anna Sinistro Antonella Cavazza Chiara Ciaprini Giovanni Rocchi Alberto Bergamini 《Cytokine》2009,45(3):190-197
CD40 ligand (CD40L) stimulation induces proinflammatory and immunomodulatory activity in monocytes. Here, we report on the effects of the steroid hormone 1α,25-dihydroxyvitamin D3 (1,25D3) on human blood monocytes that have been stimulated with the CD40L ligand. Co-treatment of CD40L-stimulated monocytes with 1,25D3 resulted in reduced production and secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, as well as in reduced expression of the surface co-stimulatory molecules CD80 and CD86. In addition, costimulation of CD4+ T lymphocytes by monocytes co-treated with CD40L and 1,25D3 resulted in reduced cell proliferation and diminished interferon (IFN)-γ but enhanced IL-10 production by CD4+ T cells. Finally, 1,25D3 interfered with the ability of CD40L to rescue monocytes from apoptosis induced by serum withdrawal. These findings suggest that 1,25D3 may regulate the interaction of monocytes with T cells or other cell types that express CD40L, thus influencing the outcome of the immune or inflammatory response. 相似文献
948.
Francesco Massart Francesca Marini Gerolamo Bianchi Salvatore Minisola Giovanni Luisetto Antonella Pirazzoli Sara Salvi Dino Micheli Laura Masi Maria Luisa Brandi 《Reproductive biology and endocrinology : RB&E》2009,7(1):32-8
Background
Skeletal characteristics such as height (Ht), bone mineral density (BMD) or bone turnover markers are strongly inherited. Common variants in the genes encoding for estrogen receptor alpha (ESR1) and beta (ESR2) are proposed as candidates for influencing bone phenotypes at the population level. 相似文献949.
Ensoli B Bellino S Tripiciano A Longo O Francavilla V Marcotullio S Cafaro A Picconi O Paniccia G Scoglio A Arancio A Ariola C Ruiz Alvarez MJ Campagna M Scaramuzzi D Iori C Esposito R Mussini C Ghinelli F Sighinolfi L Palamara G Latini A Angarano G Ladisa N Soscia F Mercurio VS Lazzarin A Tambussi G Visintini R Mazzotta F Di Pietro M Galli M Rusconi S Carosi G Torti C Di Perri G Bonora S Ensoli F Garaci E 《PloS one》2010,5(11):e13540
950.
Barbara Vagaggini Maria Laura E Bartoli Silvana Cianchetti Francesco Costa Elena Bacci Federico L Dente Antonella Di Franco Laura Malagrinò Pierluigi Paggiaro 《Respiratory research》2010,11(1):5