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)

Murine cDNAs representing distinct genes for the regulatory subunits of calmodulin-dependent protein phosphatase (CaM-PrP) were cloned from a testis library, using probes prepared by PCR amplification of brain and testis mRNA. The cDNA sequence of the brain-specific isoform (beta 1) encodes a 170 amino acid protein (M(r) approximately 19.3 kDa), whereas that for the testis isoform (beta 2) contains 179 residues (M(r) approximately 20.7 kDa); these two sequences show approximately 80% amino acid identity. An oligonucleotide probe for the brain isoform hybridized to a single mRNA of 3.6 kilobases (kb) in many tissues, whereas using the beta 2 probe, two mRNAs of 1.8 and 0.8 kb were detected only in testis. The mRNA for the testis-specific isoform increases markedly during development, its pattern being virtually identical to that of mRNA for a testicular form of the catalytic subunit (alpha 3). These data are consistent with the biological co-regulation of catalytic and regulatory subunits of a testis-specific isoenzyme during germ cell maturation.
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PMID:Structure and expression of two isoforms of the murine calmodulin-dependent protein phosphatase regulatory subunit (calcineurin B). 132 94

The expression of a regulatory subunit of calcineurin (CaN beta) during rat spermatogenesis was examined in rat testes using a monoclonal antibody Va1. Results showed that a testis-specific isoform of CaN beta was expressed only 3 weeks after birth, when meiosis begins, and increased in amount depending on the maturation of spermatogenesis. The matured sperm, which consists of only post-meiotic cells, is most likely to have only the testis-specific isoform of CaN beta. The brain type isoform of CaN beta was not detected in rat sperm. Immunoblot analysis of testes from different rodent species by a monoclonal antibody Va1 showed that all rodent species examined had their own homologues corresponding to a testis-specific isoform of CaN beta in rats, although they showed distinctively different molecular weights on SDS-PAGE compared to the testis-specific isoform in rats. Each homologue was shown to be specifically expressed in post-meiotic phase of spermatogenesis, as was seen in rats.
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PMID:The evidence for post-meiotic expression of a testis-specific isoform of a regulatory subunit of calcineurin using a monoclonal antibody. 132 57

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

Calcineurin (CN), a Ca2+/calmodulin-regulated phosphatase 2B, plays an important role in many biological processes including T-cell signal transduction. In the present study, the distribution and activity of CN were investigated in rat tissues. CN has a wide tissue distribution, as measured by enzyme-linked immunosorbent assay. CN concentrations are 0.2-0.6 micrograms/mg protein in most tissues, while the brain contains 3-10-fold higher concentrations. Immunohistochemical analyses using a monoclonal antibody to CN B subunit reveals that CN is not evenly distributed but concentrated in specific cells, especially in the brain, kidneys and testis. The specific enzymic activity of CN in tissues is around 10 pmol.min.mg protein-1, except in brain and liver (60 pmol.min-1.mg protein-1 compared to 3.6 pmol.min-1.mg protein-1). The immunosuppressants cyclosporin A and tacrolimus, but not rapamycin, inhibit the phosphatase activity of CN derived from most tissues tested, while CN activity from liver was resistant to cyclosporin A. Furthermore, transcripts and protein of the common CN B subunit and of the testis-specific form of CN B subunit were analyzed. The common CN B subunit transcripts and protein are detected in all tissues. Transcripts for the 'testis-specific' CN B subunit are also found in brain, lung, thymus and heart, while the protein is only detected in testis. This indicates that the testis-specific CN B subunit gene expression is regulated at both transcriptional and posttranscriptional levels. The findings demonstrate that CN is a widely distributed protein phosphatase and that its activity is regulated in a tissue-specific manner.
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PMID:Distribution and activity of calcineurin in rat tissues. Evidence for post-transcriptional regulation of testis-specific calcineurin B. 760 17

Immotile bovine caput epididymal sperm contain levels of protein phosphatase activity twofold higher than do mature motile caudal sperm. Comparison of the inhibition profiles of endogenous phosphatase activities detected by okadaic acid (OA) and calyculin A (CA) revealed a pattern consistent with the predominance of a type 1 protein phosphatase (PP1). Immunoblot analysis identified PP1 gamma 2 (the testis-specific isoform of PP1) as the only PP1 isoform in sperm and showed little protein phosphatase 2A (PP2A). In addition, of the known PP1 inhibitors, i.e., DARPP-32, inhibitor 1 (I1), and inhibitor 2 (I2), only I2-like activity was detected in sperm. Inhibition of PP1 by the heat-stable I2-like activity purified from sperm could be reversed with purified glycogen synthase kinase-3 (GSK-3). Furthermore, sperm extracts contain an inactive complex of PP1 and I2 (termed PP1I) that could also be activated by purified GSK-3. The presence of GSK-3 in sperm was demonstrated by activation of purified PP1I, and quantitation revealed that immotile caput sperm contained sixfold higher GSK-3 activity than motile caudal sperm. Immunoblot analysis confirmed the expression of GSK-3 in sperm and revealed the occurrence of both the alpha and beta isoforms. Our findings suggest that the higher PP1 activity measured in immotile sperm, presumably due to higher GSK-3 activity, is responsible for holding motility in check. This conclusion was supported by the observation that the phosphatase inhibitors OA and CA, at micromolar and nanomolar levels, respectively, were able to induce motility in completely immotile bovine caput epididymal sperm and to stimulate the kinetic activity of mature caudal sperm. The intrasperm levels of cAMP, pH, and calcium were unaltered by treatment with these inhibitors. The results suggest a biochemical basis for the development and regulation of sperm motility and a possible physiological role for the PP1/I2/GSK-3 system.
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PMID:Sperm motility development in the epididymis is associated with decreased glycogen synthase kinase-3 and protein phosphatase 1 activity. 883 95

Type 1 protein phosphatases (PP1) are involved in diverse cellular activities, ranging from glycogen metabolism to chromatin structure modification, mitosis, and meiosis. The holoenzymes are composed of two or more subunits, including a catalytic subunit (PP1c) and one or more regulatory subunits. Many eukaryotes possess several catalytic subunit genes which encode highly conserved isoforms. In rodents, one of these isoforms, PP1cgamma2, appears to be expressed predominantly in testes. Whether PP1cgamma2 performs a testis-specific function is unclear. To address this and other questions, the PP1cgamma gene was disrupted by targeted insertion in murine embryonic stem cells. Mice derived from these cells were viable, and homozygous females were fertile. However, males homozygous for the targeted insertion were infertile. Histological examination revealed severe impairment of spermiogenesis beginning at the round spermatid stage. In addition, defects in meiosis were inferred from the presence of polyploid spermatids. Immunohistochemistry revealed the presence of PP1calpha protein on condensing spermatids in both wild-type and mutant testes, suggesting that this closely related isoform is unable to compensate for the loss of PP1cgamma. These defects are discussed in the light of known functions of protein phosphatase 1.
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PMID:Spermiogenesis is impaired in mice bearing a targeted mutation in the protein phosphatase 1cgamma gene. 988

Complementary DNAs encoding two subunits of scallop (Patinopecten yessoensis) testis calcineurin were cloned, and the nucleotide sequences of their coding regions were determined. The deduced amino acid sequences of the catalytic subunit, calcineurin A (486 amino acid residues, M(r) 55,005.91), and the regulatory subunit, calcineurin B (170 residues, M(r) 19,237.67), showed high similarity to those of mammalian calcineurins, especially to the brain-type ones rather than to the testis-specific isoforms. Northern blot analysis showed that only a single species for each subunit was expressed in testis and the expression of each subunit increased dramatically from January to March during the maturation stages of the one-year cycle. The period when the maximum amount of mRNAs for calcineurin was expressed corresponds to the one immediately after meiosis, that is, the maturation stage in which 20-80% of the average testis is occupied by spermatozoa. The result is consistent with the one as to the expression of the testis-specific isoform of calcineurin A in mouse, which occurs immediately after meiosis. This is the first report on the stage-specific expression of calcineurin in invertebrate testis and its sequence similarity to the mammalian brain-type isoforms may indicate that the mammalian testis-specific isoforms appeared in evolution after the divergence of mammals from the mollusks and then diverged rapidly for specific functions in testis.
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PMID:Molecular cloning of cDNA encoding two subunits of calcineurin from scallop testis: demonstration of stage-specific expression during maturation of the testis. 1078 81

Two cDNAs sequences (1320 bp and 1180 bp) of the 55-kDa subunit associated with a testis-specific serine/threonine protein phosphatase 1gamma2 (PP1gamma2) were cloned. They were the same up to 1180 bp, suggesting that they may be generated by alternative splicing. Sequence studies showed that the 1320 bp-cDNA is a homolog of the human sds22alpha(1) (thus, named rat sds22alpha(1)). The 1180 bp-cDNA is a new splice-variant since its sequence at the 3' end has not been identified in human sds22 genes (named rat sds22alpha(3)). The 1320 bp-cDNA is ubiquitously expressed in various tissues including the immature testis. However, the expression of 1180 bp-cDNA was only observed in the testis after puberty. This expression pattern matches very well with that of PP1gamma2, suggesting that 1180 bp-cDNA may encode the 55-kDa subunit to associate with PP1gamma2 in rat testis and is involved in spermatogenesis by controlling PP1gamma2 activity.
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PMID:A sds22 homolog that is associated with the testis-specific serine/threonine protein phosphatase 1gamma2 in rat testis. 1089 57

Protein phosphatase 2A (PP2A) is a critical serine/threonine phosphatase involved in the control of multiple cellular functions. Distinct regulatory subunits of this holoenzyme govern its intracellular localisation and substrate specificity. The regulatory B subunits target PP2A to the substrate. The B56delta subunit encoded by Pp2r5d is expressed in different tissues including testis. Its genomic structure shows a 3' end region of 114 bp in reverse orientation complementary to the 3' region of Mea1. In mouse seminiferous epithelium Mea1 is highly expressed in pachytene spermatocytes through to spermatid cells, while Pp2r5d shows under-expression. The potential co-regulation of both these genes was analysed. However, no potential transcriptional or post-transcriptional interference between them could be fully defined. A previously unreported subunit with testis-specific expression, B56gamma-4, was characterised. This new subunit of the B56 family has no genomic structure related to Mea1, and might replace the functions of B56delta if B56delta expression were compromised by high expression of Mea1 during spermatogenesis.
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PMID:Expression of the B56delta subunit of protein phosphatase 2A and Mea1 in mouse spermatogenesis. Identification of a new B56gamma subunit (B56gamma4) specifically expressed in testis. 1505 58

Mammalian sperm were previously shown to express the PP1gamma2 isoform of protein phosphatase 1 (PP1) as well as its regulatory proteins inhibitor 2 and glycogen synthase kinase 3. Furthermore, the development of sperm motility during transit through the epididymis correlates with changes in PP1 activity. Thus, since PP1 cellular activity is determined by the partners it binds, we embarked on a study aimed at defining the specific interactomes of PP1gamma1 and PP1gamma2 (the two known alternatively spliced variants of PP1gamma). To this end, exhaustive screens were performed on a human testis cDNA library using the yeast two-hybrid method. Among the various proteins detected, the most abundant interactors with PP1gamma2 were Nek2A and R15B. Closer sequence analysis revealed novel alternatively spliced variants of Nek2A and NIPP1, which we designated Nek2A-T and NIPP1-T, respectively. They were shown to be highly expressed in rat and human testis by Northern analysis and to result from alternative splicing events by RT-PCR. Thus, both the previously known Nek2A isoform and the novel Nek2A-T and NIPP1-T variants appear to bind PP1gamma2 in vitro (blot overlays) and in vivo by coexpression in yeast. The usefulness of testis-specific alternatively spliced proteins as targets for the development of novel therapeutic strategies for male infertility and contraception is discussed. PP1gamma2, Nek2A-T, and NIPP1-T are currently being investigated as alternatively spliced targets for signal transduction therapeutics.
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PMID:Alternatively spliced protein variants as potential therapeutic targets for male infertility and contraception. 1565 32


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