Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P67775 (alpha isoform)
 797 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic ADP-ribose (cADPR) is generated in pancreatic islets by glucose stimulation, serving as a second messenger for Ca2+ mobilization from the endoplasmic reticulum for insulin secretion (Takasawa, S., Nata, K., Yonekura, H., and Okamoto, H. (1993) Science 259, 370-373). In the present study, we observed that the addition of calmodulin (CaM) to rat islet microsomes sensitized and activated the cADPR-mediated Ca2+ release. Inhibitors for CaM-dependent protein kinase II (CaM kinase II) completely abolished the glucose-induced insulin secretion as well as the cADPR-mediated and CaM-activated Ca2+ mobilization. Western blot analysis revealed that the microsomes contain the alpha isoform of CaM kinase II but do not contain CaM. When the active 30-kDa chymotryptic fragment of CaM kinase II was added to the microsomes, fully activated cADPR-mediated Ca2+ release was observed in the absence of CaM. These results along with available evidence strongly suggest that CaM kinase II is required to phosphorylate and activate the ryanodine-like receptor, a Ca2+ channel for cADPR as an endogenous activator, for the cADPR-mediated Ca2+ release.
J Biol Chem 1995 Dec 22
PMID:Requirement of calmodulin-dependent protein kinase II in cyclic ADP-ribose-mediated intracellular Ca2+ mobilization. 853 Apr 41

Peroxisome proliferators are a diverse group of rodent hepatocarcinogens that include hypolipidemic drugs, plasticizers and herbicides. These compounds when administered to rats and mice produce a dramatic increase in the size and number of hepatic peroxisomes and increase the capacity of the hepatocyte to metabolise fatty acids by inducing peroxisomal beta-oxidation enzymes such as acyl CoA oxidase. Members of the steroid hormone receptor superfamily of ligand-activated transcription factors have been identified that can be activated by peroxisome proliferators and are therefore called 'peroxisome proliferator activated receptors' (PPAR). There appear to be four PPAR isoforms within vertebrates termed alpha, beta, gamma and delta and the alpha isoform appears to be the one that is most strongly activated by synthetic peroxisome proliferators such as Wy-14,643. It has been demonstrated that PPAR alpha forms a heterodimer with the retinoid X receptor (RXR) and binds to specific DNA sequences located upstream of peroxisome proliferator responsive genes. It is therefore suggested that PPARs mediate the pleiotropic effects of peroxisome proliferators including the regulation of gene expression and rodent hepatocarcinogenesis. Rodents fed a high-fat diet develop peroxisome proliferation and many of the enzymes induced by peroxisome proliferators are involved in fatty acid metabolism. Furthermore, PPARs are activated by a wide range of fatty acids and hypolipidemic drugs, such as clofibrate, that lower triglyceride levels in man. Although it remains to be determined whether fatty acids and peroxisome proliferators bind directly to any PPAR these data suggest that the natural role of PPARs in man is to regulate lipid homeostasis. Interestingly, hypolipidaemic drugs fail to elicit peroxisome proliferation in human hepatocytes although hypolipidaemic effects are observed in patients. A further understanding of the role of PPAR in man will require: (1) the identification of additional human PPARs combined with functional analyses using these and other nuclear receptors that can antagonise PPAR action; (2) a comparison of the expression of these different receptors in human tissues; (3) a clearer understanding of how peroxisome proliferators and fatty acids activate PPAR; and (4) sequence analysis of the regulatory regions in the human counterparts of rodent peroxisome proliferator responsive genes. Together, these data will provide an important mechanism-based framework to assess the hazard of peroxisome proliferators to humans.
Mutat Res 1995 Dec
PMID:PPAR: a mediator of peroxisome proliferator action. 853 17

1. The properties of a recently identified isoform of the human muscle nicotinic acetylcholine receptor (AChR) alpha subunit (alpha +), which in muscle is expressed at similar levels to the alpha subunit, were investigated by both electrophysiological and biochemical approaches following expression in Xenopus laevis oocytes. The single-channel properties of adult (alpha 2 beta delta epsilon) and fetal (alpha 2 beta delta gamma) forms of the human AChR were also investigated. 2. The mean burst duration of adult channels (4.1 +/- 0.3 ms, mean +/- S.E.M., n = 5) is half that of fetal channels (7.9 +/- 0.6 ms, n = 4), while the single-channel conductance is larger (62.2 +/- 0.8 and 37.9 +/- 1.6 pS for adult and fetal channels, respectively), comparable to the developmental changes in single-channel properties observed for other mammalian species. 3. In contrast to the alpha isoform, the alpha + subunit does not bind 125I-labelled alpha-bungarotoxin or monoclonal antibodies directed against the AChR 'main immunogenic region' (MIR), illustrating why the alpha + subunit was first detected through screening of cDNA libraries. 4. By using site-directed mutagenesis to produce subunits that conferred different single-channel conductances on the AChR, we demonstrate that the alpha + isoform is not integrated into functional AChRs. 5. The mutagenesis experiments also revealed that the two alpha subunits within an AChR pentamer are not equivalent within the pore lining region.
J Physiol 1995 Dec 15
PMID:Functional and non-functional isoforms of the human muscle acetylcholine receptor. 878 41

We report the isolation from mouse testis cDNA of two novel RXR alpha isoforms, mRXR alpha 2 and mRXR alpha 3, with distinct sequences upstream of exon 2. These two isoforms encode a similar protein (mRXR alpha 2/3) which lacks that 28 N-terminal amino acid residues of the major RXR alpha isoform, mRXR alpha 1. The N-terminal activation function (AF-1) of mRXR alpha 2/3 appears altered when compared to that of mRXR alpha 1. mRXR alpha 2 and mRXR alpha 3 are specifically expressed in the testis, and their expression is strongly upregulated in this tissue at puberty. These observations increase the molecular complexity of RXRs, and indicate that RXR alpha may play a specific function during spermatogenesis.
Biochem Biophys Res Commun 1996 Dec 04
PMID:Two novel RXR alpha isoforms from mouse testis. 895 8

Site-specific DNA cleavage by topoisomerase II (EC 5.99.1.3) is induced by many antitumour drugs. Although human cells express two genetically distinct topoisomerase II isoforms, thus far the role and determinants of drug-induced DNA cleavage have been examined only for alpha. Here we report the first high-resolution study of amsacrine (mAMSA) induced DNA breakage by human topoisomerase II beta (overexpressed and purified from yeast) and a direct comparison with the recombinant alpha isoform. DNA cleavage in plasmid pBR322 and SV40 DNA was induced by alpha or beta in the absence or presence of the antitumour agent mAMSA, and sites were mapped using sequencing gel methodology. Low-resolution studies indicated that recombinant human alpha promoted DNA breakage at sites akin to those of beta, although some sites were only cleaved by one enzyme and different intensities were observed at some sites. However, statistical analysis of 70 drug-induced sites for beta and 70 sites for alpha revealed that both isoforms share the same base preferences at 13 positions relative to the enzyme cleavage site, including a very strong preference for A at +1. The result for recombinant alpha isoform is in agreement with previous studies using alpha purified from human cell lines. Thus, alpha and beta proteins apparently form similar ternary complexes with mAMSA and DNA. Previous studies have emphasized the importance of DNA topoisomerase II alpha; the results presented here demonstrate that beta is an in vitro target with similar site determinants, strongly suggesting that beta should also be considered a target of mAMSA in vivo.
Biochem Pharmacol 1996 Dec 13
PMID:Amsacrine-promoted DNA cleavage site determinants for the two human DNA topoisomerase II isoforms alpha and beta. 898 29

By a number of criteria, we have demonstrated that the translation termination factor eRF1 (eukaryotic release factor 1) associates with protein phosphatase 2A (PP2A). Trimeric PP2A1 was purified from rabbit skeletal muscle using an affinity purification step. In addition to the 36 kDa catalytic subunit (PP2Ac) and established regulatory subunits of 65 kDa (PR65) and 55 kDa (PR55), purified preparations contained two proteins with apparent Mrs of 54 and 55 kDa. Protein microsequencing revealed that the 55 kDa component is a novel protein, whereas the 54 kDa protein was identified as eRF1, a protein that functions in translational termination as a polypeptide chain release factor. Using the yeast two-hybrid system, human eRF1 was shown to interact specifically with PP2Ac, but not with the PR65 or PR55 subunits. By deletion analysis, the binding domains were found to be located within the 50 N-terminal amino acids of PP2Ac, and between amino acid residues 338 and 381 in the C-terminal part of human eRF1. This association also occurs in vivo, since PP2A can be co-immunoprecipitated with eRF1 from mammalian cells. We observed a significant increase in the amount of PP2A associated with the polysomes when eRF1 was transiently expressed in COS1 cells, and eRF1 immunoprecipitated from those fractions contained associated PP2A. Since we did not observe any dramatic effects of PP2A on the polypeptide chain release activity of eRF1 (or vice versa), we postulate that eRF1 also functions to recruit PP2A into polysomes, thus bringing the phosphatase into contact with putative targets among the components of the translational apparatus.
EMBO J 1996 Dec 16
PMID:The catalytic subunit of protein phosphatase 2A associates with the translation termination factor eRF1. 900 91

The role of the mammalian target of rapamycin (mTOR) was investigated in insulin responsive cell lines. mTOR was expressed at high levels in insulin responsive cell types and in 3T3-L1 cells mTOR expression levels increased dramatically as cells differentiated from fibroblasts into insulin responsive adipocytes. mTOR localized to membrane fractions in all cells tested and in 3T3-L1 adipocytes mTOR was specifically localized to microsomal membranes. Protein kinase activity directed towards mTOR was tightly associated with mTOR immunoprecipitates and this kinase activity was inhibited by FKBP12-rapamycin indicating it was due to an autokinase activity present in mTOR. The mTOR autokinase and the protein kinase activity of the p110 alpha isoform of PI 3-kinase shared several notable similarities; (a) both were maximally active in the presence of Mn2+ but also showed significant activity in the presence of Mg2+ (b) neither were inhibited by the presence of non-ionic detergent and (c) both were inhibited by wortmannin and LY294002, known inhibitors of the PI 3-kinase lipid kinase activity. These data taken together indicate the autokinase activity lay in the PI 3-kinase homology domain. In summary mTOR is a membrane anchored protein kinase that is active in conditions encountered in vivo and the fact it is highly expressed in insulin responsive cell types is consistent with a role in insulin signalling.
Biochem Biophys Res Commun 1997 Dec 29
PMID:Expression, enzyme activity, and subcellular localization of mammalian target of rapamycin in insulin-responsive cells. 943 72

In aged mice, the redox-regulated transcription factor nuclear factor-kappaB (NF-kappaB) becomes constitutively active in many tissues, as well as in cells of the hematopoietic system. This oxidative stress-induced activity promotes the production of a number of pro-inflammatory cytokines, which can contribute to the pathology of many disease states associated with aging. The administration to aged mice of agents capable of activating the alpha isoform of the peroxisome proliferator-activated receptor (PPARalpha) was found to restore the cellular redox balance, evidenced by a lowering of tissue lipid peroxidation, an elimination of constitutively active NF-kappaB, and a loss in spontaneous inflammatory cytokine production. Aged animals bearing a null mutation in PPARalpha failed to elicit these changes following treatment with PPARalpha activators, but remained responsive to vitamin E supplementation. Aged C57BL/6 mice were found to express reduced transcript levels of PPARalpha and the peroxisome-associated genes acyl-CoA oxidase and catalase. Supplementation of these aged mice with PPARalpha activators or with vitamin E caused elevations in these transcripts to levels seen in young animals. Our results suggest that PPARalpha and the genes under its control play a role in the evolution of oxidative stress excesses observed in aging.
J Biol Chem 1998 Dec 04
PMID:Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging. 983 30

Interleukin 3 (IL-3) stimulates the net growth of murine factor-dependent NSF/N1.H7 and FDC-P1/ER myeloid cells by stimulating proliferation and suppressing apoptosis. Recently, we discovered that Bcl2 is phosphorylated at an evolutionarily conserved serine residue (Ser70) after treatment with the survival agonists IL-3 or bryostatin 1, a potent activator of protein kinase (Ito, T., Deng, X., Carr, B., and May, W. S. (1997) J. Biol. Chem. 272, 11671-11673). In addition, an intact Ser70 was found to be required for Bcl2's ability to suppress apoptosis after IL-3 withdrawal or toxic chemotherapy. We now show that phosphorylation of Bcl2 occurs rapidly after the addition of agonist to IL-3-deprived cells and can be reversed by the action of an okadaic acid (OA)-sensitive phosphatase. A role for protein phosphatase (PP) 2A as the Bcl2 regulatory phosphatase is supported by several observations: 1) dephosphorylation of Bcl2 is blocked by OA, a potent PP1 and PP2A inhibitor; 2) intracellular PP2A, but not PP1, co-localizes with Bcl2; 3) the purified PP2Ac catalytic subunit directly dephosphorylates Bcl2 in vitro in an OA-sensitive manner; 4) the purified PP2Ac catalytic subunit preferentially dephosphorylates Bcl2 in vitro compared with PP1 and PP2B; 5) reciprocal immunoprecipitation studies indicate a direct interaction between PP2A and hemagglutinin (HA)-Bcl2; and 6) treatment of factor-deprived cells with bryostatin 1 dramatically increases the association between PP2A and Bcl2. Increased association between Bcl2 and PP2A occurs 15 min after agonist stimulation when Bcl2 phosphorylation has peaked and immediately before dephosphorylation. An agonist-induced increased association of PP2A and Bcl2 fails to occur in cells expressing the inactive, phosphorylation-negative S70A Bcl2 mutant, which indicates that an intact Ser70 site is necessary and sufficient for the interaction to occur. Functional phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A.
J Biol Chem 1998 Dec 18
PMID:Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. 985 76

Morphological evidence of a temporal parallelism between the appearance of the alpha isoform of protein kinase C (PKC) and some processes such as synaptogenesis in the plexiform layers of the chicken retina is offered. Immunostaining experiments were performed throughout embryonic, young and adult chicken life. The results help to understand the development of rod bipolar cells.
Brain Res Dev Brain Res 1999 Dec 10
PMID:Protein kinase C-like immunoreactive cells in embryo and adult chicken retinas. 1061 24


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