UNIPROT:P67775 - FACTA Search

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Query: UNIPROT:P67775 (alpha isoform)
797 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of simian virus 40 (SV40) large T antigen to catalyze the initiation of viral DNA replication is regulated by its phosphorylation state. Previous studies have identified the free catalytic subunit of protein phosphatase 2A (PP2Ac) as the cellular phosphatase which can remove inhibitory phosphoryl groups from serines 120 and 123. The catalytic C subunit exists in the cell complexed with a 65-kDa A subunit and one of several B subunits. To determine if any of the holoenzymes could activate T antigen, we tested the ability of the heterodimeric AC and two heterotrimeric ABC forms to stimulate T-antigen function in unwinding the origin of SV40 DNA replication. Only free catalytic subunit C and the heterotrimeric form with a 72-kDa B subunit (PP2A-T72) could stimulate T-antigen-dependent origin unwinding. Both the dimeric form (PP2A-D) and the heterotrimer with a 55-kDa B subunit (PP2A-T55) actively inhibited T-antigen function. We found that PP2A-T72 activated T antigen by dephosphorylating serines 120 and 123, while PP2A-D and PP2A-T55 inactivated T antigen by dephosphorylating the p34cdc2 target site, threonine 124. Thus, alterations in the subunit composition of PP2A holoenzymes have significant functional consequences for the initiation of in vitro SV40 DNA replication. The regulatory B subunits of PP2A may play a role in regulating SV40 DNA replication in infected cells as well.
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PMID:Different oligomeric forms of protein phosphatase 2A activate and inhibit simian virus 40 DNA replication. 800 66

To examine the role of DNA topoisomerase II (Topo II) in the mitogenic activation of mouse lymphocytes, we applied the Topo II inhibitor VM26 throughout the stimulation period and monitored morphological and functional parameters of lymphocyte activation. Cell viability and the usual increase in cell size were little affected at doses between 0.05 and 0.5 microM. DNA synthesis, however, was already significantly inhibited at 0.05 microM, with RNA synthesis inhibited to a lesser extent. Light microscope autoradiography showed that a smaller proportion of cells entered S phase, with each S phase cell incorporating less [3H]thymidine. In immunofluorescence studies, the nucleolar antigen fibrillarin was reduced, although only minor effects on the snRNP Sm antigen and the internal component labeled by antibody PI1 were observed. At the electron microscope level, nucleoli were remodeled and chromatin became aggregated. At a high dose of VM26 (5 microM), cells showed the expected high levels of apoptosis and strong inhibition in all activation parameters assayed. The results support the hypothesis that the Topo II beta isoform is involved in the very early phases of lymphocyte activation, with function of the Topo II alpha isoform, which is more sensitive to VM26, being required for progression through S phase.
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PMID:Role of topoisomerase II in the structural and functional evolution of mitogen-stimulated lymphocyte nuclei. 808 36

Heterotrimeric G proteins consisting of alpha, beta, and gamma subunits couple sensory, hormone, and neurotransmitter receptors to intracellular and transmembrane effectors. Several splicing variants of the GS (the G protein that stimulates adenylyl cyclase) alpha subunit (GS alpha) have been described. Some of these couple receptors to stimulation of adenylyl cyclase and Ca2+ channels, whereas others encode truncated proteins whose functions are not currently defined. We describe a 1321N1 human astrocytoma cDNA clone for a novel GS alpha isoform isolated from astrocytoma cells (G(astro)) that is identical to GS alpha-1 with the exception of a novel 5' sequence extending into the previously described exon 1 of GS alpha, a single base change, and an alternative polyadenylation site. Analysis by northern blotting and reverse transcription/PCR confirms the presence of an mRNA corresponding to this cDNA in astrocytoma cells. Additional northern analysis indicates that G(astro) recognizes two novel GS alpha mRNAs in the rat: a 2.0-kb mRNA expressed only in neural and neuroendocrine tissues and a 1.8-kb mRNA that is ubiquitously expressed. Functional analysis of G(astro) is complicated by the apparent insertion of alphoid satellite DNA into the transcription unit. The resulting cDNA encodes a truncated protein that may be translated from the methionine in exon 2 as previously described.
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PMID:Isolation and characterization of a novel cDNA which identifies both neural-specific and ubiquitously expressed GS alpha mRNAs. 833 49

The gene for the alpha isoform of the catalytic subunit of human protein phosphatase 2A (PPP2CA) was localized to chromosome 5 using somatic cell hybrids, and then more finely mapped to chromosome region 5q23-->q31 by in situ hybridization using a tritiated cDNA probe. The gene for the beta isoform of the catalytic subunit of this enzyme (PPP2CB) was mapped by the polymerase chain reaction to human chromosome 8 using somatic cell hybrids. Fluorescence in situ hybridization was then used to localize the PPP2CB gene to 8p12-->p11.2, using a mixture of three genomic probes that ranged from 3.5 to 8 kb in size. Finally, Southern blot analysis of somatic cell hybrid DNA suggested that a PPP2CB catalytic subunit pseudogene (PPP2CBP) is on chromosome 16.
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PMID:Localization of the genes encoding the catalytic subunits of protein phosphatase 2A to human chromosome bands 5q23-->q31 and 8p12-->p11.2, respectively. 838 90

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.
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PMID:PPAR: a mediator of peroxisome proliferator action. 853 17

Certain protein kinase C (PKC) isotypes are localized to the nucleus during cellular proliferation in murine erythroid cells, as well as in human promyelocytic leukemia and erythroleukemia cells. Because the structure of these PKC isotypes contains a conserved cysteine-rich region that contains the zinc finger DNA binding motif, we tested the hypothesis that selected PKC isotypes found in Friend erythroleukemia cells can bind to DNA. Cell lysates from murine Friend erythroleukemia cells, which express alpha, beta I, and beta II PKC, expressed greater amounts of the beta isoforms than the alpha isoform of PKC in their nuclei, and PKC beta I was found in the chromatin of these cells. Lysates of these cells were tested for their ability to bind to a DNA-cellulose column. Bound proteins were eluted with a step gradient of increasing KCl concentrations, and eluant fractions were then subjected to immunoblot analysis using isotype-specific antibodies to the alpha and beta I isotypes of PKC. DNA binding was detected for the PKC beta I isotype, which is present in the nucleus, but not for the more abundant PKC alpha isotype, which resides primarily in the cytoplasm. These results demonstrate that PKC can associate with DNA, and that this association is isotype specific in Friend erythroleukemia cells.
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PMID:Protein kinase C beta from Friend erythroleukemia cells is associated with chromatin and DNA. 856 55

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.
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PMID:Amsacrine-promoted DNA cleavage site determinants for the two human DNA topoisomerase II isoforms alpha and beta. 898 29

The transcription factor hepatocyte nuclear factor 4 (HNF4) is an orphan member of the nuclear receptor superfamily expressed in mammals in liver, kidney, and the digestive tract. Recently, we isolated the Xenopus homolog of mammalian HNF4 and revealed that it is not only a tissue-specific transcription factor but also a maternal component of the Xenopus egg and distributed within an animal-to-vegetal gradient. We speculate that this gradient cooperates with the vegetally localized embryonic induction factor activin A to activate expression of HNF1alpha, a tissue-specific transcription factor with an expression pattern overlapping that of HNF4. We have now identified a second Xenopus HNF4 gene, which is more distantly related to mammalian HNF4 than the previously isolated gene. This new gene was named HNF4beta to distinguish it from the known HNF4 gene, which is now called HNF4alpha. By reverse transcription-PCR, we detected within the 5' untranslated region of HNF4beta two splice variants (HNF4beta2 and HNF4beta3) with additional exons, which seem to affect RNA stability. HNF4beta is a functional transcription factor acting sequence specifically on HNF4 binding sites known for HNF4alpha, but it seems to have a lower DNA binding activity and is a weaker transactivator than the alpha isoform. Furthermore, the two factors differ with respect to tissue distribution in adult frogs: whereas HNF4alpha is expressed in liver and kidney, HNF4beta is expressed in addition in stomach, intestine, lung, ovary, and testis. Both factors are maternal proteins and present at constant levels throughout embryogenesis. However, using reverse transcription-PCR, we found the RNA levels to change substantially: whereas HNF4alpha is expressed early during oogenesis and is absent in the egg, HNF4beta is first detected in the latest stage of oogenesis, and transcripts are present in the egg and early cleavage stages. Furthermore, zygotic HNF4alpha transcripts appear in early gastrula and accumulate during further embryogenesis, whereas HNF4beta mRNA transiently appears during gastrulation before it accumulates again at the tail bud stage. All of these distinct characteristics of the newly identified HNF4 protein imply that the alpha and beta isoform have different functions in development and in adult tissues.
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PMID:HNF4beta, a new gene of the HNF4 family with distinct activation and expression profiles in oogenesis and embryogenesis of Xenopus laevis. 900 Dec 22

Isoforms of DNA polymerase alpha (pol alpha/primase; pol alpha) were isolated from the livers of C57BL/6 mice either 3 months old (young) or 13 months old (mature). The 13-month-old mice were from two groups, one in which food was available ad libitum (AL), and one in which calories had been restricted to 60% of the AL intake (CR). The polymerases from young vs. mature and CR vs. AL mice differed in total and specific pol alpha activity, with the highest values exhibited by enzymes from 3-month-old mice. A more active isoform of pol alpha was typically isolated from CR animals than from AL animals. Differences in charge were used to chromatographically separate pol alpha into elution peaks exhibiting differing degrees of enzyme activity. DNA pol alpha isolated from tissues of mature mice exhibited a decline in activity which was not associated with decreased recoverable levels of pol alpha protein, but with a decline in the tendency of pol alpha to co-purify with an accessory protein, alpha AP, that binds double-stranded DNA (dsDNA). Low activity pol alpha isoforms which did not co-purify with alpha AP were stimulated by interaction with exogenous alpha AP. Pol alpha isoforms which co-purified with the dsDNA-binding accessory protein exhibited higher specific activity and less enhancement of activity upon interaction with exogenous alpha AP. Calorie restricted animals exhibited a pol alpha isoform that was more like pol alpha from younger animals in that it typically copurified with alpha AP, the DNA-binding accessory protein.
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PMID:An accessory protein of DNA polymerase alpha declines in function with increasing age. 906 22

Acquisition of heat shock factor 2 (HSF2) DNA binding activity is accompanied by induced transcription of heat shock genes in hemin-treated K562 cells undergoing erythroid differentiation. Previous studies revealed that HSF2 consists of two alternatively spliced isoforms, HSF2-alpha and HSF2-beta, whose relative abundance is developmentally regulated and varies between different tissues. To investigate whether the molar ratio of HSF2-alpha and HSF2-beta isoforms is crucial for the activation of HSF2 and whether the HSF2 isoforms play functionally distinct roles during the hemin-mediated erythroid differentiation, we generated cell clones expressing different levels of HSF2-alpha and HSF2-beta. We show that in parental K562 cells, the HSF2-alpha isoform is predominantly expressed and HSF2 can be activated upon hemin treatment. In contrast, when HSF2-beta is expressed at levels exceeding those of endogenous HSF2-alpha, the hemin-induced DNA binding activity and transcription of heat shock genes are repressed, whereas overexpression of HSF2-alpha results in an enhanced hemin response. Furthermore, the hemin-induced accumulation of globin, known as a marker of erythroid differentiation, is decreased in cells overexpressing HSF2-beta. We suggest that HSF2-beta acts as a negative regulator of HSF2 activity during hemin-mediated erythroid differentiation of K562 cells.
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PMID:Overexpression of HSF2-beta inhibits hemin-induced heat shock gene expression and erythroid differentiation in K562 cells. 918 56

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