Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

A cDNA for an alternatively spliced variant of the testis-specific catalytic subunit of calmodulin dependent protein phosphatase (CaM-PrP) was cloned from a human testis library. The nucleotide sequence of 2134 base pairs (bp) encodes a protein of 502 amino acids (Mr approximately 57,132) and pI 7.0. The cDNA sequence differs from the murine form of this gene by a 30 bp deletion in the coding region, the position of which matches those in the two other genes for the catalytic subunit. These data indicate that this alternative splicing event arose prior to the divergence of the three genes. The deduced sequence of the human protein is only 88% identical to the homologous murine form, in striking contrast to the other two CaM-PrP catalytic subunits which are highly conserved between mouse and human (approximately 99%); this indicates a more rapid rate of evolution for the testis-specific gene. Analysis of Southern blots containing DNA from human-hamster somatic cell hybrids show that the gene is on human chromosome 8.
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PMID:Molecular cloning and chromosomal mapping of the human gene for the testis-specific catalytic subunit of calmodulin-dependent protein phosphatase (calcineurin A). 133 77

Multiple catalytic subunits of the Ca2+ and calmodulin (CaM)-dependent protein phosphatase (PrP) ("calcineurin" or PrP-2B) are derived from at least two structural genes, type 1 ("calcineurin A alpha") and type 2 ("calcineurin A beta "), each of which can produce alternatively spliced transcripts. To examine the possible linkage of these genes, we analyzed genomic DNA from human/hamster hybrid cell lines using probes of 122 base pairs that were designed to bind selectively to exon 3 of the open reading frame. In this region, the nucleotide sequence of the type 2 murine cDNA that we cloned was greater than 99% identical to the type 2 human cDNA but only 78% identical to the type 1 human cDNA. Hybridization to Southern blots containing DNA from all human chromosomes showed that gene 1 was found on chromosome 4, whereas gene 2 segregated to chromosome 10. These data suggest that expression of the two calcineurin genes is not physically linked.
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PMID:Chromosomal mapping of the human genes for the calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit. 165 8

The distribution of the mRNAs encoding the different isoforms of the catalytic subunit (A subunit) of calcineurin has been investigated in rat thymus and kidney using in situ hybridization histochemistry with specific antisense oligonucleotide probes. In the thymus, the mRNAs of the A beta isoforms were the predominant transcripts and showed very intense hybridization signals in the cortical areas. The A alpha mRNAs were expressed at low levels. A beta 2 mRNA was expressed at higher levels than A beta 3 mRNA, but no difference could be detected between the expression levels of A alpha 1 and A alpha 2. In the kidney, highest calcineurin A mRNA hybridization signals were found in the medulla. Signal intensities of A alpha mRNAs were comparable to those of A beta mRNAs. A alpha 1 mRNA level was extremely weak, and A beta 2 mRNA expression was slightly higher than A beta 3 mRNA expression. A tissue-specific distribution pattern of the alternatively spliced isoforms of calcineurin A, as suggested by these preliminary data from thymus and kidney, may be critical in understanding the toxic side-effects associated with the use of the immunosuppressive, calcineurin-inhibiting compounds cyclosporin A and FK506.
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PMID:Distribution of calcineurin A isoenzyme mRNAs in rat thymus and kidney. 763 61

Recent studies using HeLa in vitro splicing extracts have shown that changes in the relative concentrations of constitutive protein splicing factors can affect the choice between competing 5' splice sites in alternatively spliced mammalian pre-mRNAs. Here we report that treatment of a HeLa splicing extract with human protein phosphatase 1 strongly inhibits formation of mRNA spliced to the distal 5' splice site while stimulating relative use of the proximal 5' splice site. This effect is not observed if spliceosomes assemble prior to protein phosphatase 1 treatment. These data show that alternative splicing in HeLa extracts can be mediated by changes in protein modification as well as by changes in the relative concentration of splicing factors. Changes in protein phosphorylation may thus provide a rapid mechanism for cells to respond to stimuli that require an alteration in alternative splicing patterns.
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PMID:Protein phosphatase 1 can modulate alternative 5' splice site selection in a HeLa splicing extract. 792 86

Specific antisense oligonucleotide probes for the alpha isoforms of the catalytic subunit (A-subunit) of calcineurin were prepared and the distribution of A alpha 1 and A alpha 2 mRNA's has been studied in rat brain using in situ hybridization histochemistry. Clear regional differences have been observed for the A alpha 1 and A alpha 2 isoforms. The predominant form, A alpha 1, was found to be preferentially expressed in the caudate putamen, the pyramidal cell layer of the hippocampus, specific cortical cell layers, the cerebellar granular cell layer and some other brain areas. On the other hand, the A alpha 2 isoform, although being generally less abundant than A alpha 1, gave an intense autoradiography signal in the dentate gyrus of the hippocampus and was the major transcript in the amygdala, the superior and the inferior colliculus, the central gray matter and the reticular formation. These regional differences might reflect specific functions exerted by the two alternatively spliced isoenzymes in the CNS and opens the perspective of interfering with defined calcineurin-dependent signal transduction pathways using isoform-specific compounds.
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PMID:Differential distribution of calcineurin A alpha isoenzyme mRNA's in rat brain. 813 11

Differential association of regulatory B subunits with a core heterodimer, composed of a catalytic (C) and a structural (A) subunit, is an important mechanism that regulates protein phosphatase 2A (PP2A). We have isolated and characterized three novel cDNAs related to the B' subunit of bovine cardiac PP2A. Two human (B'alpha1 and B'alpha2) and a mouse (B'alpha3) cDNA encode for alternatively spliced variants of the B subunit. The deduced primary sequences of these clones contain 12 of 15 peptides derived from the purified bovine B' subunit. Differences between the deduced sequences of the B alpha splice variants and the cardiac peptide sequences suggest the existence of multiple isoforms of the B' subunit. Comparison of the protein and nucleotide sequences of the cloned cDNAs show that all three forms of B'alpha diverge at a common splice site near the 3'-end of the coding regions. Northern blot and reverse transcription-polymerase chain reaction analyses revealed that the B'alpha transcripts (4.3-4.4 kb) are widely expressed and very abundant in heart and skeletal muscle. The expressed human and mouse B'alpha proteins readily associated with the PP2A core enzyme in both in vitro and in vivo complex formation assays. Immunofluorescence microscopy revealed that epitope-tagged B'alpha was localized in both the cytosol and nuclei of transiently transfected cells. The efficiency of binding of all three expressed proteins to a glutathione S-transferase-A subunit fusion protein was greatly enhanced by the addition of the C subunit. Expression of the B'alpha subunits in insect Sf9 cells resulted in formation of AC.B'alpha heterotrimers with the endogenous insect A and C subunits. These results show that the B' subunit, which is the predominant regulatory subunit in cardiac PP2A, is a novel protein whose sequence is unrelated to other PP2A regulatory subunits. The nuclear localization of expressed B'alpha suggests that some variants of the B' subunit are involved in the nuclear functions of PP2A.
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PMID:Identification of a novel protein phosphatase 2A regulatory subunit highly expressed in muscle. 861 97

Inositol polyphosphate 4-phosphatase (4-phosphatase) is a Mg2+-independent enzyme that catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate, inositol 1,3,4-trisphosphate, and inositol 3,4-bisphosphate. We have isolated cDNA encoding a 105,257-Da protein that is 37% identical to the previously cloned 4-phosphatase. Recombinant protein was expressed in Escherichia coli and shown to hydrolyze all three 4-phosphatase substrates with enzymatic properties similar to the original enzyme. We designate the original 4-phosphatase and the new isozyme as inositol polyphosphate 4-phosphatase types I and II, respectively. 4-Phosphatase II is highly conserved with the human and rat enzymes having 90% amino acid identity. A conserved motif between 4-phosphatase I and II is the sequence CKSAKDRT that contains the Cys-Xaa5-Arg active site consensus sequence identified for other Mg2+-independent phosphatases. Northern blot analysis indicated that 4-phosphatase II is widely expressed with the highest levels occurring in the skeletal muscle and heart. In addition, cDNA encoding alternatively spliced forms of human 4-phosphatase I (107, 309 Da) and rat 4-phosphatase II (106,497 Da) were also isolated that encode proteins with a putative transmembrane domain near their C termini. These alternatively spliced forms were expressed as recombinant proteins in E. coli and SF9 insect cells and found to possess no detectable enzymatic activity suggesting that additional factors and/or processing may be required for these alternatively spliced isozymes.
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PMID:The cDNA cloning and characterization of inositol polyphosphate 4-phosphatase type II. Evidence for conserved alternative splicing in the 4-phosphatase family. 929 34

In the fission yeast Schizosaccharomyces pombe, 14 prp (pre-mRNAprocessing) mutants have been isolated to date. We cloned the prp10(+) gene by complementation of the temperature-sensitive growth of prp10. Five types of transcripts were found that were alternatively spliced with respect to two possible introns located in the 5'-terminal region. Three of them are probably functional and code for putative proteins of approximately 1200 amino acids. Proteins highly homologous to Prp10p are present in other organisms, one of which is a human spliceosome-associated protein SAP155, a subunit of the splicing factor complex SF3. The C-terminal two-thirds of Prp10p is highly conserved among species, and contains consensus repeats for the regulatory subunit A of protein phosphatase PP2A. A gene disruption experiment indicated that the prp10(+) gene is essential for viability in S.pombe. Prp10p tagged with GFP is predominantly localized in the nuclear DNA region. A series of deletions showed that the less conserved N-terminal region of approximately 300 amino acids in Prp10p is dispensable, although the corresponding region was thought to play important roles in the mammalian splicing system.
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PMID:The fission yeast prp10(+) gene involved in pre-mRNA splicing encodes a homologue of highly conserved splicing factor, SAP155. 983 97

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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