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51.
Hristina Ivanova Tim Vervliet Ludwig Missiaen Jan B. ParysHumbert De Smedt Geert Bultynck 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2014
Cell-death and -survival decisions are critically controlled by intracellular Ca2 + homeostasis and dynamics at the level of the endoplasmic reticulum (ER). Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) play a pivotal role in these processes by mediating Ca2 + flux from the ER into the cytosol and mitochondria. Hence, it is clear that many pro-survival and pro-death signaling pathways and proteins affect Ca2 + signaling by directly targeting IP3R channels, which can happen in an IP3R-isoform-dependent manner. In this review, we will focus on how the different IP3R isoforms (IP3R1, IP3R2 and IP3R3) control cell death and survival. First, we will present an overview of the isoform-specific regulation of IP3Rs by cellular factors like IP3, Ca2 +, Ca2 +-binding proteins, adenosine triphosphate (ATP), thiol modification, phosphorylation and interacting proteins, and of IP3R-isoform specific expression patterns. Second, we will discuss the role of the ER as a Ca2 + store in cell death and survival and how IP3Rs and pro-survival/pro-death proteins can modulate the basal ER Ca2 + leak. Third, we will review the regulation of the Ca2 +-flux properties of the IP3R isoforms by the ER-resident and by the cytoplasmic proteins involved in cell death and survival as well as by redox regulation. Hence, we aim to highlight the specific roles of the various IP3R isoforms in cell-death and -survival signaling. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau. 相似文献
52.
53.
Yuji Morimoto Shoichi Ishii Jun-ichi Ishibashi Kazutaka Katoh Toshifumi Tsujiuchi Nao Kagawa Nobuyuki Fukushima 《Gene》2014
Lysophosphatidic acid (LPA) signaling is known to play biological and pathophysiological roles in many types of animals. Medaka (Oryzias latipes) is an experimental fish that can be easily maintained, propagated, and analyzed, and whose genome has been completely sequenced. However, there is limited information available regarding medaka LPA receptors. Here, using information from the medaka genome database, we examine the genomic structures, expression, and functions of six LPA receptor genes, Lpar1–Lpar6. Our analyses reveal that the genomic structures of Lpar1 and Lpar4 are different from those deduced from the database. Functional analyses using a heterologous expression system demonstrate that all medaka LPA receptors except for LPA5b respond to LPA treatment with cytoskeletal changes. These findings provide useful information on the structure and function of medaka LPA receptor genes, and identify medaka as a useful experimental model for exploration of the biological significance of LPA signaling. 相似文献
54.
Chong Xu Jinfei Zhang Yijiao Xu Qian Ren Min Guo Shile Huang Long Chen 《Journal of neurochemistry》2014,128(2):256-266
Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Celastrol, a plant‐derived triterpene, has shown neuroprotective effects in various disease models. However, little is known regarding the effect of celastrol on Cd‐induced neurotoxicity. Here, we show that celastrol protected against Cd‐induced apoptotic cell death in neuronal cells. This is supported by the findings that celastrol strikingly attenuated Cd‐induced viability reduction, morphological change, nuclear fragmentation, and condensation, as well as activation of caspase‐3 in neuronal cells. Concurrently, celastrol remarkably blocked Cd‐induced phosphorylation of c‐Jun N‐terminal kinase (JNK), but not extracellular signal‐regulated kinases 1/2 and p38, in neuronal cells. Inhibition of JNK by SP600125 or over‐expression of dominant negative c‐Jun potentiated celastrol protection against Cd‐induced cell death. Furthermore, pre‐treatment with celastrol prevented Cd down‐regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and activation of phosphoinositide 3′‐kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling in neuronal cells. Over‐expression of wild‐type PTEN enhanced celastrol inhibition of Cd‐activated Akt/mTOR signaling and cell death in neuronal cells. The findings indicate that celastrol prevents Cd‐induced neuronal cell death via targeting JNK and PTEN‐Akt/mTOR network. Our results strongly suggest that celastrol may be exploited for the prevention of Cd‐induced neurodegenerative disorders.
55.
My career in research has flourished through hard work, supportive mentors, and outstanding mentees and collaborators. The Carman laboratory has contributed to the understanding of lipid metabolism through the isolation and characterization of key lipid biosynthetic enzymes as well as through the identification of the enzyme-encoding genes. Our findings from yeast have proven to be invaluable to understand regulatory mechanisms of human lipid metabolism. Several rewarding aspects of my career have been my service to the Journal of Biological Chemistry as an editorial board member and Associate Editor, the National Institutes of Health as a member of study sections, and national and international scientific meetings as an organizer. I advise early career scientists to not assume anything, acknowledge others’ accomplishments, and pay it forward. 相似文献
56.
Fragments of cancellous and cortical bone from human maxilla and mandible were cultured by the explant technique. Cells isolated by trypsinization of primary cultures were characterized as osteoblasts on the basis of intracellular alkaline phosphatase activity, the constituents of the extracellular matrix, and response to human parathormone (PTH). In culture, the osteoblasts often gave rise to superposed clumps of large cells whose cytoplasm contained endoplasmic reticulum, numerous mitochondria, vacuoles, and a dense network of intermediate filaments, often at the level of the plasma membrane. In the presence of vitamin C and 1,25-dihydroxyvitamin D3, the osteoblasts produced an extracellular matrix composed of collagen type I and various non-collagenous proteins, including osteocalcin. Biochemical test results were comparable to those reported for osteoblasts of other origins (rat calvaria, human iliac crest), and namely elevated intracellular alkaline phosphatase activity and cAMP accumulation in response to stimulation by human PTH (1–34). Osteoblasts isolated in this manner were cultured in the presence of pure titanium disks to determine the effects of exposure to this metal. Electron microscopy revealed few significant differences in cell growth and specific enzyme activity compared to control osteoblasts grown on plastic dishes, reflecting the excellent biologic and biochemical relationship between the osteoblasts and pure titanium. This experimental system thus appears suitable for biocompatibility studies, and in particular, evaluation of dental implants. 相似文献
57.
Rivera T Ghenoiu C Rodríguez-Corsino M Mochida S Funabiki H Losada A 《The EMBO journal》2012,31(6):1467-1479
Shugoshins (Sgo) are conserved proteins that act as protectors of centromeric cohesion and as sensors of tension for the machinery that eliminates improper kinetochore-microtubule attachments. Most vertebrates contain two Sgo proteins, but their specific functions are not always clear. Xenopus laevis Sgo1, XSgo1, protects centromeric cohesin from the prophase dissociation pathway. Here, we report the identification of XSgo2 and show that it does not regulate cohesion. Instead, we find that it participates in bipolar spindle assembly. Both Sgo proteins interact physically with the Chromosomal Passenger Complex (CPC) containing Aurora B, a key regulator of mitosis, but the functional consequences of such interaction are distinct. XSgo1 is required for proper localization of the CPC while XSgo2 positively contributes to its activation and the subsequent phosphorylation of at least one key substrate for bipolar spindle assembly, the microtubule depolymerizing kinesin MCAK (Mitotic Centromere-Associated Kinesin). Thus, the two Xenopus Sgo proteins have non-overlapping functions in chromosome segregation. Our results further suggest that this functional specificity could rely on the association of XSgo1 and XSgo2 with different regulatory subunits of the PP2A complex. 相似文献
58.
The intrinsic ability of vascular smooth muscle cells (VSMCs) within arterial resistance vessels to respectively contract and relax in response to elevation and reduction of intravascular pressure is essential for appropriate blood flow autoregulation. This fundamental mechanism, referred to as the myogenic response, is dependent on apposite control of myosin regulatory light chain (LC20) phosphorylation, a prerequisite for force generation, through the coordinated activity of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP). Here, we highlight the molecular basis of the smooth muscle contractile mechanism and review the regulatory pathways demonstrated to participate in the control of LC20 phosphorylation in the myogenic response, with a focus on the Ca2+-dependent and Rho-associated kinase (ROK)-mediated regulation of MLCK and MLCP, respectively. 相似文献
59.
MAP kinase phosphatase 3 (MKP3, also known as DUSP6 and PYST1) is involved in extracellular signal receptor kinase (ERK) regulation and functions as a specific phosphatase to the activated (phosphorylated) forms of ERK1 and ERK2. MKP3 displays allosteric activation, which aids in tightly regulating its function to ERK substrates, but not other related MAPKs. Due to MKP3's specificity for the ERK signaling pathway, the development of specific activators or inhibitors to the enzyme have been suggested in order to expressly influence the ERK1 and ERK2 pathways. To produce the high yields of MKP3 protein necessary for physico-chemical characterization of MKP3 and for high throughput screening of its small-molecule activators and inhibitors, we have cloned, purified and, and identified refolding conditions suitable for producing full-length, human MKP3 from Escherichia coli inclusion bodies. Furthermore, we demonstrate the use of a 96-well plate format refolding assay in which the ERK-induced activity of MKP3 is simulated by 33% DMSO. The assay allowed for rapid detection of MKP3's function following a refolding screen in the absence of ERK and thus provides quick and inexpensive testing of MKP3 activity. Following screening, the refolded product was confirmed to be correctly folded by steady-state kinetic analysis and by the CD spectroscopy-determined secondary structure content. CD data were consistent with 36% helix and 14% sheet, which compared to an expected 32.9% helix and 12.4% sheet. These data indicated that MKP3 was properly folded, making it a suitable protein for use in functional studies. 相似文献
60.
Association of dystrobrevin and regulatory subunit of protein kinase A: a new role for dystrobrevin as a scaffold for signaling proteins 总被引:1,自引:0,他引:1
Ceccarini M Grasso M Veroni C Gambara G Artegiani B Macchia G Ramoni C Torreri P Mallozzi C Petrucci TC Macioce P 《Journal of molecular biology》2007,371(5):1174-1187
The dystrophin-related and -associated protein dystrobrevin is a component of the dystrophin-associated protein complex, which directly links the cytoskeleton to the extracellular matrix. It is now thought that this complex also serves as a dynamic scaffold for signaling proteins, and dystrobrevin may play a role in this context. Since dystrobrevin involvement in signaling pathways seems to be dependent on its interaction with other proteins, we sought new insights and performed a two-hybrid screen of a mouse brain cDNA library using beta-dystrobrevin, the isoform expressed in non-muscle tissues, as bait. Among the positive clones characterized after the screen, one encodes the regulatory subunit RIalpha of the cAMP-dependent protein kinase A (PKA). We confirmed the interaction by in vitro and in vivo association assays, and mapped the binding site of beta-dystrobrevin on RIalpha to the amino-terminal region encompassing the dimerization/docking domain of PKA regulatory subunit. We also found that the domain of interaction for RIalpha is contained in the amino-terminal region of beta-dystrobrevin. We obtained evidence that beta-dystrobrevin also interacts directly with RIIbeta, and that not only beta-dystrobrevin but also alpha-dystrobrevin interacts with PKA regulatory subunits. We show that both alpha and beta-dystrobrevin are specific phosphorylation substrates for PKA and that protein phosphatase 2A (PP2A) is associated with dystrobrevins. Our results suggest a new role for dystrobrevin as a scaffold protein that may play a role in different cellular processes involving PKA signaling. 相似文献