Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NIPP-1 was originally isolated as a potent and specific nuclear inhibitory polypeptide (16-18 kDa) of protein phosphatase-1. We report here the cDNA cloning of NIPP-1 from bovine thymus and show that the native polypeptide consists of 351 residues and has a calculated mass of 38.5 kDa. The bacterially expressed central third of NIPP-1 completely inhibited the type-1 catalytic subunit, but displayed a reduced inhibitory potency after phosphorylation by protein kinase A and casein kinase 2. Translation of NIPP-1 mRNA in reticulocyte lysates resulted in the accumulation of both intact NIPP-1 and a smaller polypeptide generated by alternative initiation at the codon corresponding to Met143. A data base search showed that the COOH terminus of NIPP-1 is nearly identical to the human ard-1 protein (13 kDa), which has been implicated in RNA processing (Wang, M., and Cohen, S. N. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 10591-10595). Comparison of the cDNAs encoding ard-1 and NIPP-1 suggests that their mRNAs are generated by alternative splicing of the same pre-mRNA. Western blotting with antibodies against the COOH terminus of NIPP-1, however, showed a single polypeptide of 47 kDa, which was enriched in the nucleus. Northern analysis revealed a single transcript of 2.2 kilobases in bovine thymus and of 2.4 kilobases in various human tissues.
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PMID:Molecular cloning of NIPP-1, a nuclear inhibitor of protein phosphatase-1, reveals homology with polypeptides involved in RNA processing. 749 93

The activity of protein phosphatase-1 in rat liver nuclei (PP-1N) was decreased by up to 97% by associated inhibitory polypeptides, depending on the assay and extraction conditions. These inhibitors were rapidly degraded by endogenous proteases, resulting in the accumulation of active heat-stable intermediates. Two major species of PP-1N could be differentiated by fractionation of a nuclear extract. PP-1NR111 contained, besides the delta-isoform of the catalytic subunit, an inhibitory polypeptide of 111 kDa. PP-1NR41 was found to be an inactive heterodimer between the delta-isoform of the catalytic subunit and NIPP-1, a nuclear inhibitor of PP-1, which in its undegraded form is heat labile and migrates during SDS-polyacrylamide gel electrophoresis as a polypeptide of 41 kDa. Native hepatic NIPP-1 displayed a reduced affinity for the catalytic subunit after phosphorylation by protein kinase A in vitro and after glucagon-induced phosphorylation in vivo.
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PMID:Subunit structure and regulation of protein phosphatase-1 in rat liver nuclei. 761 25

Bovine thymus nuclei contain a species of protein phosphatase-1 (PP-1N alpha) that can be partially activated by phosphorylation of an associated inhibitory polypeptide, NIPP-1, with protein kinase A [Beullens, Van Eynde, Bollen and Stalmans (1993) J. Biol. Chem. 268, 13172-13177]. Here it is shown that PP-1N alpha can also be activated 4-fold by phosphorylation of NIPP-1 with casein kinase-2. The effects of protein kinase A and casein kinase-2 were additive, yielding an enzyme with an activity close to that of the free catalytic subunit. Casein kinase-2 introduced up to 1.2 phosphate groups into purified NIPP-1 on serine and threonine residues. This phosphorylation was associated with a 14-fold increase in the concentration of NIPP-1 required for 50% inhibition of the type-1 catalytic subunit. The kinase-mediated inactivation of NIPP-1 could be reversed by incubation with the catalytic subunit of protein phosphatase-2A.
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PMID:Full activation of a nuclear species of protein phosphatase-1 by phosphorylation with protein kinase A and casein kinase-2. 811 Jan 79

We have recently purified two potent and specific inhibitory polypeptides of protein phosphatase-1 from the particulate fraction of bovine thymus nuclei (Beullens, M., Van Eynde, A., Stalmans, W., and Bollen, M. (1992) J. Biol. Chem. 267, 16538-16544). Here it is reported that these inhibitors, termed NIPP-1a (18 kDa) and NIPP-1b (16 kDa), are excellent substrates (Km = 0.1 microM) for phosphorylation by protein kinase A on both Ser and Thr residues. Phosphorylation was temporally closely related with an activation of NIPP-1. Maximal phosphorylation by protein kinase A (1.5 mol of phosphate/mol of NIPP-1) caused an 8-fold increase in the concentration of NIPP-1 required for half-complete inhibition of the catalytic subunit of protein phosphatase-1, irrespective of the concentration of the phosphatase. Phosphorylation decreased the binding of NIPP-1 to immobilized protein phosphatase-1. NIPP-1 could be efficiently and completely reactivated by incubation with the catalytic subunit of protein phosphatase-2A. The type-1 catalytic subunit was much less effective, however, even when present in a molar excess to NIPP-1. Chromatography of a salt extract of the particulate nuclear fraction of Mono Q revealed three species of PP-1. One of these species, termed PP-1N alpha, contained NIPP-1 as a subunit and could be activated 6-fold by incubation with protein kinase A under phosphorylating conditions. This activation of PP-1N alpha is opposite to the known inhibition of cytoplasmic species of protein phosphatase-1 by protein kinase A.
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PMID:Inactivation of nuclear inhibitory polypeptides of protein phosphatase-1 (NIPP-1) by protein kinase A. 839 Apr 58

The human ARD-1 (activator of RNA decay) cDNA sequence can rescue mutations in the Escherichia coli rne gene, which specifies the essential endoribonuclease RNase E, resulting in RNase E-like cleavages in vivo in rne-defective bacteria and in vitro in extracts isolated from these cells (Wang, M., and Cohen, S. N. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 10591-10595). Recent studies indicate that the 13.3-kDa protein encoded by ARD-1 cDNA is almost identical to the carboxyl-terminal end of the bovine protein NIPP-1, a nuclear inhibitor of protein phosphatase 1; separate transcripts formed by alternative splicing are proposed to encode the discrete ARD-1 and combined ARD-1/NIPP-1 products (Van Eynde, A., Wera, S., Beullens, M. , Torrekens, S., Van Leuven, F., Stalmans, W., and Bollens, M. (1995) J. Biol. Chem. 270, 28068-28074). Here we show that affinity column-purified protein encoded by human ARD-1 cDNA in E. coli is a site-specific Mg2+-dependent endoribonuclease that binds in vitro to RNase E substrates, cleaves RNA at the same sites as RNase E, and, like RNase E, generates 5' phosphate termini at sites of cleavage. Our results indicate that the ARD-1 peptide can function as a ribonucleolytic analog of E. coli RNase E as well as a domain of the protein phosphatase inhibitor, NIPP-1.
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PMID:ARD-1 cDNA from human cells encodes a site-specific single-strand endoribonuclease that functionally resembles Escherichia coli RNase E. 915 39

Transient transfection of COS-1 cells with an expression vector for NIPP-1, a nuclear subunit of protein phosphatase-1, did not result in an overexpression of NIPP-1 protein, although the levels of mRNA encoding NIPP-1 increased dramatically. Moreover, high concentrations of NIPP-1 mRNA inhibited the translation in reticulocyte lysates of various unrelated mRNAs. This inhibition of translation was caused by the NIPP-1 messenger and not by the translation product, since mutation of the start codon abolished NIPP-1 protein production, but had no influence on the translational inhibition. Analysis of deletion mutants showed that the inhibition was mediated by a 0.5-kb fragment in the 5'-end of the NIPP-1 mRNA. This region, when inserted in the 5'-untranslated region of the beta-galactosidase messenger, inhibited the translation of beta-galactosidase mRNA in COS-1 cells. A predicted highly stable secondary structure deltaG = -239.5 kJ/mol) is present between residues 300 and 500 of NIPP-1 mRNA. The possible importance of this structure in the translational inhibition is discussed.
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PMID:Inhibition of translation by mRNA encoding NIPP-1, a nuclear inhibitor of protein phosphatase-1. 924 54

NIPP-1 is a nuclear inhibitory subunit of protein phosphatase-1 with structural similarities to some proteins involved in RNA processing. We report here that baculovirus-expressed recombinant NIPP-1 displays RNA-binding properties, as revealed by North-Western analysis, by UV-mediated cross-linking, by RNA mobility-shift assays, and by chromatography on poly(U)-Sepharose. NIPP-1 preferentially bound to U-rich sequences, including RNA-destabilizing AUUUA motifs. NIPP-1 also associated with single-stranded DNA, but had no affinity for double-stranded DNA. The binding of NIPP-1 to RNA was blocked by antibodies directed against the COOH terminus of NIPP-1, but was not affected by prior phosphorylation of NIPP-1 with protein kinase A or casein kinase-2, which decreases the affinity of NIPP-1 for protein phosphatase-1. The catalytic subunit of protein phosphatase-1 did not bind to poly(U)-Sepharose, but it bound very tightly after complexation with NIPP-1. These data are in agreement with a function of NIPP-1 in targeting protein phosphatase-1 to RNA.
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PMID:NIPP-1, a nuclear inhibitory subunit of protein phosphatase-1, has RNA-binding properties. 926 47

Various studies have provided evidence for the existence of spontaneously active cytosolic species of protein phosphatase 1, but these enzymes have never been purified and characterized. We have used chromatography on microcystin-Sepharose and Resource Q to purify cytosolic protein phosphatases from rat liver. Two of the isolated enzymes were identified by Western analysis and peptide sequencing as complexes of the catalytic subunit of protein phosphatase 1 and either the inhibitor NIPP1 or the myosin-binding subunit MYPT1, which reportedly is not present in chicken liver. In contrast, PCR cloning revealed the expression of two MYPT1 splice variants in rat liver.
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PMID:Identification of MYPT1 and NIPP1 as subunits of protein phosphatase 1 in rat liver cytosol. 1042 96

NIPP1 (351 residues) is a major regulatory and RNA-anchoring subunit of protein phosphatase 1 in the nucleus. Using recombinant and synthetic fragments of NIPP1, the RNA-binding domain was mapped to the C-terminal residues 330-351. A synthetic peptide encompassing this sequence equalled intact NIPP1 in RNA-binding affinity and could be used to dissociate NIPP1 from the nuclear particulate fraction. An NIPP1 fragment consisting of residues 225-351 (Ard1/NIPP1gamma), that may be encoded by an alternatively spliced transcript in transformed B-lymphocytes, displayed a single-strand Mg(2+)-dependent endoribonuclease activity. However, full-length NIPP1 and NIPP1(143-351) were not able to cleave RNA, indicating that the endoribonuclease activity of NIPP1 is restrained by its central domain. The endoribonuclease activity was also recovered in the RNA-binding domain, NIPP1(330-351), but with a 30-fold lower specific activity. Thus, the endoribonuclease catalytic site and the RNA-binding site both reside in the C-terminal 22 residues of NIPP1. The latter domain does not conform to any known nucleic-acid binding motif.
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PMID:Mapping of the RNA-binding and endoribonuclease domains of NIPP1, a nuclear targeting subunit of protein phosphatase 1. 1043 94

ARD-1 is an endoribonuclease identified initially as the product of a human cDNA that complements mutations in rne, a gene that encodes Escherichia coli ribonuclease E. NIPP-1 was identified in bovine nuclear extracts as an inhibitor of protein phosphatase-1. Earlier work has shown that the protein-coding sequence of ARD-1 is identical to the carboxy-terminal third of NIPP-1. However, whether ARD-1 is present in eukaryotes as a distinct entity has been unclear, as neither ARD-1-specific transcripts nor ARD-1 protein were detected in mammalian cells in earlier studies. Here we show that ARD-1 exists in human cells as a discrete protein, and that the ARD-1 and NIPP-1 peptides are isoforms encoded by a single gene and the same alternatively spliced precursor RNA. A retained intron containing multiple translation stop codons that are configured to terminate translation and initiate nonsense-mediated decay, limits the production of cellular ARD-1 protein. Our results establish the process by which functionally disparate ARD-1 and NIPP-1 peptides are generated from the protein-coding sequence of the same gene in human cells.
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PMID:Alternative splicing regulates the production of ARD-1 endoribonuclease and NIPP-1, an inhibitor of protein phosphatase-1, as isoforms encoded by the same gene. 1056 11


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