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)

To check the anti-apoptosis gene bcl-2 protein/mRNA expression in 28 acute promyelocytic leukemia (APL), by immunohistochemistry and in situ hybridization, and to analyse the relationship among the bcl-2 gene expressions, clinical prognosis and classification of the isoforms of fuse gene in APL. The result shows the two types of isoforms of PML-RAR alpha have no significance in bcl-2 protein/mRNA expression, indexes of clinical prognosis. This shows that the classification of PML-RAR alpha isoform has no influence on clinical prognosis.
Hunan Yi Ke Da Xue Xue Bao 2000 Dec 28
PMID:[The relationship between clinical prognosis and classification of the isoforms of fuse gene in acute promyelocytic leukemia]. 1251 5

In our recent reports, the novel isoform cDNAs of the ER alpha (ER alpha isoform S cDNA), ER beta (ER beta isoform M cDNA) and PR (PR isoform S and PR isoform T cDNAs) have been identified. These isoform cDNAs contained the previously unidentified 5'-sequences on exons 4-8 (ER alpha isoform S cDNA), exons 5-8 (ER beta isoform M cDNA) or exons 4-8 (PR isoform S and PR isoform T cDNAs). The genomic DNA analysis revealed that the 5'-sequences were derived from the novel independent exons, the ER alpha exon S, ER beta exon M, PR exon S and PR exon T, respectively. Furthermore, the existence of the novel variant mRNA, termed the i45 PR mRNA variant, with the insertion of the previously unidentified exons, termed the exons i45a and i45b, has been demonstrated by the reverse transcription-polymerase chain reaction on the RNA of the human uterine endometrium. From these results, we have concluded that the genes for the human female sex steroid hormone receptors contain the novel intronic exons, that the novel isoform mRNAs are transcribed using the intronic exon and exons 4-8 (or exons 5-8) of the gene, and that the novel variant mRNA is generated by the insertion of the intronic exons in the PR. In the present communication, our recent data along with others on the novel isoform/variant mRNAs for the human female sex steroid hormone receptors will be summarized.
J Steroid Biochem Mol Biol 2002 Dec
PMID:Novel isoforms of the mRNA for human female sex steroid hormone receptors. 1265 Jun 98

The proteome contains hundreds of proteins that in theory could be excellent therapeutic targets for the treatment of human diseases. However, many of these proteins are from functional classes that have never been validated as viable candidates for the development of small molecule inhibitors. Thus, to exploit fully the potential of the Human Genome Project to advance human medicine, there is a need to develop generic methods of inhibiting protein activity that do not rely on the target protein's function. We previously demonstrated that a normally stable protein, methionine aminopeptidase-2 or MetAP-2, could be artificially targeted to an Skp1-Cullin-F-box (SCF) ubiquitin ligase complex for ubiquitination and degradation through a chimeric bridging molecule or Protac (proteolysis targeting chimeric molecule). This Protac consisted of an SCF(beta-TRCP)-binding phosphopeptide derived from IkappaBalpha linked to ovalicin, which covalently binds MetAP-2. In this study, we employed this approach to target two different proteins, the estrogen (ER) and androgen (AR) receptors, which have been implicated in the progression of breast and prostate cancer, respectively. We show here that an estradiol-based Protac can enforce the ubiquitination and degradation of the alpha isoform of ER in vitro, and a dihydroxytestosterone-based Protac introduced into cells promotes the rapid disappearance of AR in a proteasome-dependent manner. Future improvements to this technology may yield a general approach to treat a number of human diseases, including cancer.
Mol Cell Proteomics 2003 Dec
PMID:Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. 1452 58

Inhibition of Na,K-ATPase activity by cardiac glycosides is believed to be the major mechanism by which this class of drugs increases heart contractility. However, direct evidence demonstrating this is lacking. Furthermore it is unknown which specific alpha isoform of Na,K-ATPase is responsible for the effect of cardiac glycosides. Several studies also suggest that cardiac glycosides, such as ouabain, function by mechanisms other than inhibition of the Na,K-ATPase. To determine whether Na,K-ATPase, specifically the alpha2 Na,K-ATPase isozyme, mediates ouabain-induced cardiac inotropy, we developed animals expressing a ouabain-insensitive alpha2 isoform of the Na,K-ATPase using Cre-Lox technology and analyzed cardiac contractility after administration of ouabain. The homozygous knock-in animals were born in normal Mendelian ratio and developed normally to adulthood. Analysis of their cardiovascular function demonstrated normal heart function. Cardiac contractility analysis in isolated hearts and in intact animals demonstrated that ouabain-induced cardiac inotropy occurred in hearts from wild type but not from the targeted animals. These results clearly demonstrate that the Na,K-ATPase and specifically the alpha2 Na,K-ATPase isozyme mediates ouabain-induced cardiac contractility in mice.
J Biol Chem 2003 Dec 26
PMID:The alpha2 isoform of Na,K-ATPase mediates ouabain-induced cardiac inotropy in mice. 1455 19

E-6375 (4-butoxy-2-[4-(2-cyanobenzoyl)-1-piperazinyl] pyrimidine hydrochloride) is a new intravenous general anaesthetic with an anaesthetic potency, in mice, comparable to propofol, or etomidate. Here, we examined the effect of E-6375 upon the GABAA receptor, a putative target of intravenous anaesthetic action. E-6375 reversibly enhanced GABA-evoked currents mediated by recombinant GABAA (alpha1beta2gamma2L) receptors expressed in Xenopus laevis oocytes, with little effect on NMDA- and kainate-evoked currents mediated by NR1a/NR2A and GluR1o/GluR2o glutamate receptors, respectively. E-6375 prolonged the decay of GABA-evoked miniature inhibitory postsynaptic currents recorded from rat Purkinje neurones demonstrating the anaesthetic also enhanced the activity of synaptic GABAA receptors. The GABA enhancing action of E-6375 on recombinant GABAA receptors was unaffected by the subtype of the alpha isoform (i.e. alphaxbeta2gamma2L; x=1-3) within the receptor, but was increased by the omission of the gamma2L subunit. Receptors incorporating beta2, or beta3, subunits were more sensitive to modulation by E-6375 than those containing the beta1 subunit. The selectivity of E-6375 was largely governed by the identity (serine or asparagine) of a single amino acid residue within the second transmembrane domain of the beta-subunit. The various in vivo actions of general anaesthetics may be mediated by GABAA receptor isoforms that have a differential distribution within the CNS. The identification of agents, such as E-6375, that discriminate between GABAA receptor subtypes may augur the development of general anaesthetics with an improved therapeutic profile.
Neuropharmacology 2003 Dec
PMID:GABAA receptor modulation by the novel intravenous general anaesthetic E-6375. 1461 46

Neonatal hypoxia-ischemia (HI) can result in significant sensorimotor abnormalities, including movement and posture disorders. These neurological impairments are believed to result from basal ganglia (striatum) damage, but the exact cause of this injury is not known. One mechanism involved in brain injury after HI is the generation of reactive oxygen species, which damage cellular macromolecules. We tested the hypothesis that inactivation of plasma membrane enzyme Na,K-ATPase during striatal neurodegeneration after HI emerges with peroxynitrite attack on the enzyme. In vitro, reaction of peroxynitrite (100-500 microM) with purified Na,K-ATPase produced nitration of the alpha (catalytic) and beta (transport) subunits, as quantified by immunoblots of the reaction products for nitrotyrosine. To evaluate for peroxynitrite damage to Na,K-ATPase in vivo, striatal plasma membrane fractions from 1-week-old piglets subjected to asphyxic cardiac arrest and recovery were also studied by immunoprecipitation. During the progression of striatal neurodegeneration and loss of enzyme function 3-24 h after arrest, nitration of the alpha3 (neuronal) isoform of Na,K-ATPase was not increased relative to sham control. Suprisingly, however, nitration of this alpha isoform occurs during normal brain development and peaks at 2 weeks of age. We conclude that Na,K-ATPase is a target of peroxynitrite, but that this mechanism is not responsible for enzyme inactivation after HI. Protein nitration may serve as marker of other normal, noninjurious cell processes in the developing brain.
Neurochem Res 2003 Dec
PMID:Nitration of the striatal Na,K-ATPase alpha3 isoform occurs in normal brain development but is not increased during hypoxia-ischemia in newborn piglets. 1464 31

The LIM homeodomain protein Islet-1 (Isl1), one of the earliest markers for motor neuron differentiation, is also expressed in all classes of islet cells in the pancreas. Isl1 is known to bind and regulate the promoters of the insulin, glucagon and somatostatin genes. In this study, we describe isolation of a novel isl1 cDNA species from the mouse islet beta cell line betaTC6, which arose from the utilization of an alternative splicing acceptor site in the fifth exon. This shorter cDNA encodes an Isl1 isoform (Isl1-beta) lacking the carboxy-terminal 23 amino acids of the previously reported product Isl1-alpha. Although the level of isl1-beta mRNA is much lower than that of isl1-alpha, isl1-beta is preferentially expressed in murine insulinoma cell lines but not in glucagonoma cell line. Upon transient transfection, both Isl1-alpha and Isl1-beta accumulate in the nuclei of murine insulinoma cells. We found that Isl1-beta is a relatively more potent transcriptional activator of the insulin promoter than Isl1-alpha and that the Isl1-alpha isoform undergoes phosphorylation. Therefore, the transcriptional activity of Isl1 is potentially regulated by the alternative splicing of its mRNA and by phosphorylation.
J Mol Endocrinol 2003 Dec
PMID:Isolation and characterization of an alternatively spliced variant of transcription factor Islet-1. 1466 3

GNAS is a complex imprinted gene that uses multiple promoters to generate several gene products, including the G protein alpha-subunit (G(s)alpha) that couples seven-transmembrane receptors to the cAMP-generating enzyme adenylyl cyclase. Somatic activating G(s)alpha mutations, which alter key residues required for the GTPase turn-off reaction, are present in various endocrine tumors and fibrous dysplasia of bone, and in a more widespread distribution in patients with McCune- Albright syndrome. Heterozygous inactivating G(s)alpha mutations lead to Albright hereditary osteodystrophy. G(s)alpha is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in renal proximal tubules, thyroid, pituitary, and ovary. Maternally inherited mutations lead to Albright hereditary osteodystrophy (AHO) plus PTH, TSH, and gonadotropin resistance (pseudohypoparathyroidism type 1A), whereas paternally inherited mutations lead to AHO alone. Pseudohypoparathyroidism type 1B, in which patients develop PTH resistance without AHO, is almost always associated with a GNAS imprinting defect in which both alleles have a paternal-specific imprinting pattern on both parental alleles. Familial forms of the disease are associated with a mutation within a closely linked gene that deletes a region that is presumably required for establishing the maternal imprint, and therefore maternal inheritance of the mutation results in the GNAS imprinting defect. Imprinting of one differentially methylated region within GNAS is virtually always lost in pseudohypoparathyroidism type 1B, and this region is probably responsible for tissue-specific G(s)alpha imprinting. Mouse knockout models show that G(s)alpha and the alternative G(s)alpha isoform XLalphas that is expressed from the paternal GNAS allele may have opposite effects on energy metabolism in mice.
Endocrinology 2004 Dec
PMID:Minireview: GNAS: normal and abnormal functions. 1533 75

Folates are essential for cell survival and are required for numerous biochemical processes. The human alpha isoform folate receptor (alphahFR) has a very high affinity for folic acid and is considered an essential component in the cellular accumulation of folates and folate analogues used in chemotherapy. The expression of alphahFR is not detected inmost normal tissues. In contrast, high levels of the expression of alphahFR have been reported in a variety of cancer cells. The significance of alphahFR overexpression in malignant tissues has not been elucidated, but it is possible that it promotes cell proliferation not only by mediating folate uptake but also by generating other regulatory signals. The purpose of the present study was to evaluate alphahFR as a potential target for the treatment of breast cancer. Initial studies were done in nasopharyngeal carcinoma (KB) cells, which express high levels of alphahFR. In KB cells, antisense oligodeoxyribonucleotides (ODN) complementary to the alphahFR gene sequences were found to reduce newly synthesized alphahFR protein up to 60%. To examine the effect of alphahFR antisense ODNs in a panel of cultured human breast cancer cell lines, we used a tumor cell-targeted, transferrin-liposome-mediated delivery system. The data show that alphahFR antisense ODNs induced a dose-dependent decrease in cell survival. Finally, we determined that alphahFR antisense ODNs sensitized MDA-MB-435 breast cancer cells by 5-fold to treatment with doxorubicin. The data support the application of alphahFR antisense ODNs as a potential anticancer agent in combination with doxorubicin.
Mol Cancer Ther 2004 Dec
PMID:Antisense oligonucleotides targeted to the human alpha folate receptor inhibit breast cancer cell growth and sensitize the cells to doxorubicin treatment. 1563 43

The monoclonal antibody (mAb) MOv18 binds the membrane alpha isoform of the folate receptor (FR) which is overexpressed in human ovarian carcinoma cells. Exploiting the targeting capacity of this mAb, we developed and preclinically validated a protocol for the stable labeling of the mAb with 90Y, an isotope which has shown promise in cancer radioimmunotherapy. MOv18 was derivatized with the stable macrocyclic ligand p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (Bz-DOTA). MOv18-Bz-DOTA conjugates were labeled with 90Y or 111In under metal-free and good laboratory practice conditions. At the optimal Bz-DOTA/mAb derivatization ratio of 4-5, conjugates maintained binding activity up to 6 months, were efficiently labeled with 90Y or 111In (mean labeling yield 85 and 64%, associated to a final mean specific activity of 74 and 37 MBq/mg) and displayed a mean immunoreactivity of 60 and 58%, respectively. The radiolabeled preparations were stable in human serum, with >97% radioactivity associated to mAb at 48 h after labeling. The ability of 90Y- and 111In-MOv18 to localize FR on tumors in vivo was analyzed in nude mice bearing tumors induced by isogenic cell lines differing only in the presence or absence of the relevant antigen [A431FR (FR-positive) and A431tMock (FR-negative)]. In vivo biodistribution in organs other than tumor was comparable in non-tumor-, A431tMock- and A431FR-bearing mice, whereas the median tumor uptake of the radiolabeled reagents, expressed as area under the curve (AUC) and maximum uptake (Umax), was significantly higher (sixfold to sevenfold) in A431FR than in A431tMock tumors (P=0.0465 and P=0.0332, respectively). Mean maximum uptake (% ID/g) for 90Y-MOv18 was 53.7 and 7.4 in A431FR and A431tMock respectively; corresponding values for 111In-Mov18 were 45.0 and 11.3. These data demonstrate the feasibility of 90Y-labeling of MOv18 without compromising antibody binding ability and the immunoreagent-specific localization in vivo on FR-expressing tumors, suggesting the suitability of 90Y-MOv18 for clinical studies.
Cancer Immunol Immunother 2005 Dec
PMID:90Y Labeling of monoclonal antibody MOv18 and preclinical validation for radioimmunotherapy of human ovarian carcinomas. 1592 78


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