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71.
72.
Cyclin-dependent kinase 5 phosphorylates serine 31 of tyrosine hydroxylase and regulates its stability 总被引:2,自引:0,他引:2
Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis, and its activity is regulated by phosphorylation in the N-terminal regulatory domain. The proline-directed serine/threonine kinase cyclin-dependent kinase 5 (cdk5) plays an important role in diverse neuronal processes. In the present study, we identify TH as a novel substrate of cdk5. We show that cdk5 phosphorylates TH at serine 31 and that this phosphorylation is associated with an increase in total TH activity. In transgenic mice with increased cdk5 activity, the immunoreactivity for phosphorylated TH at Ser-31 is enhanced in neurons of the substantia nigra, a brain region enriched with TH-positive neurons. In addition, we demonstrate that co-expression of cdk5 and its regulatory activator p35 with TH increases the stability of TH. Consistent with these findings, TH protein levels are reduced in cdk5 knock-out mice. Importantly, the TH activity and protein turnover of the phosphorylation-defective mutant TH S31A was not altered by cdk5 activity. Taken together, these data suggest that cdk5 phosphorylation of TH is an important regulator of TH activity through stabilization of TH protein levels. 相似文献
73.
74.
This protocol describes a method for making and culturing rat hippocampal organotypic slices on membrane inserts. Supplementary videos are included to demonstrate visually the different steps of the procedure. Cultured hippocampal slices has been increasingly used as a model for synaptic studies of the brain as they allow examination of mid to long term manipulations in a preparation where the gross cytoarchitecture of the hippocampus is preserved. Combining techniques such as molecular biology, electrophysiology and immunohistochemistry to study physiological or pathological processes can easily be applied to organotypic slices. The technique described here can be used to make organotypic slices from other parts of the brain, other rodent species and from a range of ages. This protocol can be completed in 3 h. 相似文献
75.
Three polymorphisms of the glutamate decarboxylase 2 gene, which encodes the glutamic acid decarboxylase enzyme, have been associated with severe obesity in a large French cohort. One of these polymorphisms was shown to have functional consequences on promoter expression. Another polymorphism was associated with insulin levels and secretion. These associations were examined in 855 severely obese Utah subjects (mean BMI = 48 kg/m(2)) and a normal-weight and normoglycemic subset (N = 130, mean BMI = 22 kg/m(2)) of a random sample of the Utah population (N = 462). Comparisons of the normal-weight random group with the severely obese group did not result in significant genotype or allele frequency differences for any of the three polymorphisms, C61450A, T83897A, or A-243G (all p > or = 0.18). Haplotypes were also not related to severe obesity (p = 0.10). None of the polymorphisms was significantly related to fasting glucose, insulin levels, or homeostasis model assessment insulin resistance or secretion indices. This study of normal-weight and severely obese subjects from Utah does not provide evidence for involvement of the three genotyped polymorphisms in the glutamate decarboxylase 2 gene with obesity or with insulin- and glucose-related measures associated with obesity. 相似文献
76.
Tang K Utairungsee T Kanokratana P Sriprang R Champreda V Eurwilaichitr L Tanapongpipat S 《FEMS microbiology letters》2006,260(1):91-99
A novel gene belonging to the alpha-amylase family was isolated directly from community DNA obtained from soil sediments collected from Bor Khleung hot spring in Thailand. Partial sequences harboring four conserved regions of the alpha-amylase family were amplified by PCR using degenerate primers. Upstream and downstream sequences of these fragments were obtained by a genome walking approach to identify a full-length gene (Env cda13A) encoding 619 amino acids. Amino acid sequence alignments of Env Cda13A with other enzymes suggested that this enzyme was a cyclomaltodextrinase. The Env cda13A gene was expressed in Pichia pastoris as a secreted functional protein of 68 kDa. The partially purified enzyme was shown to be monomeric and hydrolyzed various maltodextrins from maltotriose to maltoheptaose and cyclomaltodextrins to give maltose and glucose as the main products. The enzyme also hydrolyzed pullulan and soluble starch to yield glucose, but the rate of hydrolysis was slow. This study demonstrated the possibility of isolating potentially novel enzymes directly from natural environments and opens an unexplored biodiversity resource in Thailand for future novel gene discoveries. 相似文献
77.
Das-Chatterjee A Goswami L Maitra S Dastidar KG Ray S Majumder AL 《FEBS letters》2006,580(16):3980-3988
We have previously demonstrated that introgression of PcINO1 gene from Porteresia coarctata (Roxb.) Tateoka, coding for a novel salt-tolerant L-myo-inositol 1-phosphate synthase (MIPS) protein, confers salt tolerance to transgenic tobacco plants (Majee, M., Maitra, S., Dastidar, K.G., Pattnaik, S., Chatterjee, A., Hait, N.C., Das, K.P. and Majumder, A.L. (2004) A novel salt-tolerant L-myo-inositol-1-phosphate synthase from Porteresia coarctata (Roxb.) Tateoka, a halophytic wild rice: molecular cloning, bacterial overexpression, characterization, and functional introgression into tobacco-conferring salt-tolerance phenotype. J. Biol. Chem. 279, 28539-28552). In this communication we have shown that functional introgression of the PcINO1 gene confers salt-tolerance to evolutionary diverse organisms from prokaryotes to eukaryotes including crop plants albeit to a variable extent. A direct correlation between unabated increased synthesis of inositol under salinity stress by the PcINO1 gene product and salt tolerance has been demonstrated for all the systems pointing towards the universality of the application across evolutionary divergent taxa. 相似文献
78.
Liu N Meng Z Lou G Zhou W Wang X Zhang Y Zhang L Liu X Yen Y Lai L Forman BM Xu Z Xu R Huang W 《Molecular endocrinology (Baltimore, Md.)》2012,26(5):775-785
Farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4) is a member of nuclear hormone receptor superfamily, which plays essential roles in metabolism of bile acids, lipid, and glucose. We previously showed spontaneously hepatocarcinogenesis in aged FXR(-/-) mice, but its relevance to human hepatocellular carcinoma (HCC) is unclear. Here, we report a systematical analysis of hepatocarcinogenesis in FXR(-/-) mice and FXR expression in human liver cancer. In this study, liver tissues obtained from FXR(-/-) and wild-type mice at different ages were compared by microarray gene profiling, histological staining, chemical analysis, and quantitative real-time PCR. Primary hepatic stellate cells and primary hepatocytes isolated from FXR(-/-) and wild-type mice were also analyzed and compared. The results showed that the altered genes in FXR(-/-) livers were mainly related to metabolism, inflammation, and fibrosis, which suggest that hepatocarcinogenesis in FXR(-/-) mice recapitulated the progression of human liver cancer. Indeed, FXR expression in human HCC was down-regulated compared with normal liver tissues. Furthermore, the proinflammatory cytokines, which were up-regulated in human HCC microenvironment, decreased FXR expression by inhibiting the transactivity of hepatic nuclear factor 1α on FXR gene promoter. Our study thereby demonstrates that the down-regulation of FXR has an important role in human hepatocarcinogenesis and FXR(-/-) mice provide a unique animal model for HCC study. 相似文献
79.
Central neurons respond to synaptic inputs from other neurons by generating synaptic potentials. Once the summated synaptic potentials reach threshold for action potential firing, the signal propagates leading to transmitter release at the synapse. The calcium influx accompanying such signaling opens calcium-activated ion channels for feedback regulation. Here, we report a mechanism for modulating hippocampal neuronal signaling that involves calcium-activated chloride channels (CaCCs). We present evidence that CaCCs reside in hippocampal neurons and are in close proximity of calcium channels and NMDA receptors to shorten action potential duration, dampen excitatory synaptic potentials, impede temporal summation, and raise the threshold for action potential generation by synaptic potential. Having recently identified TMEM16A and TMEM16B as CaCCs, we further show that TMEM16B but not TMEM16A is important for hippocampal CaCC, laying the groundwork for deciphering the dynamic CaCC modulation of neuronal signaling in neurons important for learning and memory. 相似文献
80.
Gray NE Lam LN Yang K Zhou AY Koliwad S Wang JC 《The Journal of biological chemistry》2012,287(11):8444-8456
Intracellular triacylglycerol (TG) hydrolysis and fatty acid release by the white adipose tissue (WAT) during a fast is stimulated by counter-regulatory factors acting in concert, although how adipocytes integrate these lipolytic inputs is unknown. We tested the role of angiopoietin-like 4 (Angptl4), a secreted protein induced by fasting or glucocorticoid treatment, in modulating intracellular adipocyte lipolysis. Glucocorticoid receptor blockade prevented fasting-induced tissue Angptl4 expression and WAT TG hydrolysis in mice, and TG hydrolysis induced by fasts of 6 or 24 h was greatly reduced in mice lacking Angptl4 (Angptl4(-/-)). Glucocorticoid treatment mimicked the lipolytic effects of fasting, although with slower kinetics, and this too required Angptl4. Thus, fasting-induced WAT TG hydrolysis requires glucocorticoid action and Angptl4. Both fasting and glucocorticoid treatment also increased WAT cAMP levels and downstream phosphorylation of lipolytic enzymes. Angptl4 deficiency markedly reduced these effects, suggesting that Angptl4 may stimulate lipolysis by modulating cAMP-dependent signaling. In support of this, cAMP levels and TG hydrolysis were reduced in primary Angptl4(-/-) murine adipocytes treated with catecholamines, which stimulate cAMP-dependent signaling to promote lipolysis, and was restored by treatment with purified human ANGPTL4. Remarkably, human ANGPTL4 treatment alone increased cAMP levels and induced lipolysis in these cells. Pharmacologic agents revealed that Angptl4 modulation of cAMP-dependent signaling occurs upstream of adenylate cyclase and downstream of receptor activation. We show that Angptl4 is a glucocorticoid-responsive mediator of fasting-induced intracellular lipolysis and stimulates cAMP signaling in adipocytes. Such a role is relevant to diseases of aberrant lipolysis, such as insulin resistance. 相似文献