Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyphosphoinositide isomers have been demonstrated to be important mediators of cell proliferation in vitro. The present study demonstrates, for the first time, the in vivo formation of the novel isomer, phosphatidylinositol(3)phosphate, in the kidney and liver of intact animals following intraperitoneal administration of [3H]myo-inositol. The formation of renal [3H]phosphatidylinositol(3)phosphate relative to total [3H]phosphatidylinositol-phosphate was positively correlated with cyst proliferation and renal enlargement in a murine model of polycystic kidney disease. Furthermore, despite no difference in the formation of renal [3H]phosphatidylinositol(4)phosphate, a markedly lower accumulation (by 48%) of [3H]phosphatidylinositol(4,5)bisphosphate was observed in the diseased animals as compared to controls. These results indicate that further studies on the in vivo formation of specific polyphosphoinositide isomers in disease states characterized by abnormal growth and oncogene expression are warranted.
Exp Mol Pathol 1992 Aug
PMID:In vivo formation of polyphosphoinositide isomers and association with progression of murine polycystic kidney disease. 132 62

Cells from the cysts of patients with autosomal dominant polycystic kidney disease (PKD) were grown in vitro under standard conditions without the aid of collagen-pretreated surfaces, and both the synthesis and composition of the extracellular matrix were investigated. At confluence, PKD cells presented the typical features of epithelial cells, but showed a different collagen composition from fibroblasts. Compared with normal tubular epithelia (NTE), PKD monolayers produced an excess of extracellular matrix, which accounted for 30% of the total incorporation of [3H] proline, although this value was considerably lower (by a factor of 10) in the case of NTE. Immunohistochemical and electrophoretic techniques revealed a complex collagen composition in the extracellular matrix which included [alpha (III)]3 and collagen IV. However, part of the collagen components remained unidentified in spite of the fact that they exhibited a typical M(r) of alpha 1(I) and alpha 2(I) in the presence of urea. Immunoprecipitation with monospecific antibodies and Northern blotting with specific probes failed to recognize alpha 1(I) and alpha 2(I), but demonstrated their presence in fibroblasts. Purification and cyanogen bromide digestion demonstrated a strong interhomology in fingerprint peptide composition among the uncharacterized collagens synthesized by PKD cells, thus suggesting a common identity. These observations document a markedly augmented production of extracellular matrix by PKD cultured cells in vitro, and show the presence of collagens which do not share homologies with the major collagen molecules. A better characterization of extracellular matrix composition is central to any comprehension of the cytogenetic mechanisms in vivo.
Virchows Arch B Cell Pathol Incl Mol Pathol 1992
PMID:Extracellular matrix formation by epithelial cells from human polycystic kidney cysts in culture. 136 16

Three hundred fifteen radiation hybrids (RH) were isolated using a monochromosomal cell hybrid containing chromosome 16 only. A panel of 18 RH, which showed breakpoints among four markers (3.15, 26.6, 3'HVR, and 5'HVR) mapping in the distal portion of 16p, were selected and characterized for the retention of nine additional DNA sequences already localized in this region, and for one centromeric sequence. One or more breakpoints were identified in nine of the 12 intervals defined by the 13 single-copy sequences used. This panel of RH represents a tool for the construction of a detailed physical map of the distal part of 16p and for cloning sequences located in the proximity of disease genes. Three inter-Alu DNA sequences, amplified from one of these RH containing the autosomal dominant polycystic kidney disease (PKD1) gene, were cloned and mapped in the panel. Sequencing of the ends of one of three clones showed a (CAAA)n repeat, which revealed a two-allele polymorphism.
Somat Cell Mol Genet 1992 Jul
PMID:Radiation hybrids for mapping and cloning DNA sequences of distal 16p. 144 54

The induction of polycystic kidney disease (PKD) by glucocorticoids in newborn mice behaves as a "threshold" trait, with prevalence of PKD varying in different inbred strains after exposure to an inducing steroid. C3H mice (low threshold for PKD) demonstrated greater specific dexamethasone binding than DBA mice (high threshold) on the second day of life. Treatment with methylprednisolone acetate (MPA), a cyst-inducing steroid, down regulated dexamethasone binding earlier than in DBA mice. C3H mice demonstrated greater whole kidney homogenate Na-K ATPase activity than DBA mice within 24h of MPA injection. Specific renal glucocorticoid binding may be a regulator of threshold for murine glucocorticoid induced PKD. Our findings support in vitro evidence that glucocorticoid induced Na-K ATPase activity during critical periods of nephron development is an important regulatory point of this model.
J Steroid Biochem Mol Biol 1991 Aug
PMID:Ontogeny of dexamethasone binding and sodium potassium ATPase activity in experimental murine polycystic kidney disease. 165 92

The major form of autosomal dominant polycystic kidney disease (ADPKD) in humans is linked to the PKD1 gene on chromosome 16p. The identity of the gene and the underlying pathogenetic mechanisms are not yet defined. Cyst-lining epithelial cells derived from a polycystic kidney were successfully grown in culture and designated MZ-PKD-1 cells. By linkage analysis, the related pedigree of the nephrectomized patient could be linked to the PKD1 gene on chromosome 16p. Thus, these cells exhibit the genotype of a mutated PKD1 gene and represent an in vitro culture model for ADPKD involving chromosome 16p. The antigenic phenotype was characterized immunohistologically by epithelial differentiation antigens and markers of individual nephron segments. An essentially identical antigenic pattern of proximal tubular cells was observed both in vitro and in fresh frozen tissue. Electron microscopy showed the formation of a microvillous-like coating. During growth phases in vitro successive changes in the cell shape were observed. MZ-PKD-1 cells exhibited a limited lifespan ending in replicative senescence. Northern blot analysis of kidney-growth-related genes, c-myc, TGF-alpha, TGF-beta 1, and EGF receptor revealed abundant expression of all of these genes in MZ-PKD-1 cells.
Virchows Arch B Cell Pathol Incl Mol Pathol 1991
PMID:Autosomal dominant polycystic kidney disease--in vitro culture of cyst-lining epithelial cells. 168 80

Reactive oxygen species are generated physiologically in cells with a significant increase in certain pathological conditions, such as inflammation, cancer, aging, degenerative disease. If endogenous antioxidant systems, in our study represented by glutathione peroxidase, are exceeded by this oxidant flux, tissue injury may occur. Activity of glutathione peroxidase (GPx) was determined using Beutler's modified spectrophotometric assay in erythrocytes from autosomal dominant polycystic kidney disease patients. Activity of glutathione peroxidase was significantly (at p < 0.0001) lower there (17.75 +/- 3.69 U/g haemoglobin) compared to the control group (23.26 +/- .61 U/g Hb). Lower antioxidant enzyme defence system of ADPKD patients, here represented by GPx, can potentiate injury caused by free radicals and possibly play a role in the progression of autosomal dominant polycystic kidney disease.
Biochem Mol Biol Int 1995 Apr
PMID:Activity of the antioxidant enzyme, glutathione peroxidase, on autosomal dominant polycystic kidney disease patients. 762 19

We previously identified a gene from the mutant locus in a new mouse mutation that causes recessive polycystic kidney disease. Here we describe the cloning, characterization and mapping of the homologous human gene. The human and mouse genes are 95% identical at the predicted amino acid sequence level, and both genes encode a putative protein that contains a tetratricopeptide repeat motif. The human gene, called hTg737, is expressed with a broad tissue distribution that includes the the kidney and liver, and gives rise to a 2.9 kb mRNA. The gene contains 26 exons and spans a genomic region greater than 100 kb. Chromosome mapping experiments revealed that the hTg737 gene maps near the centromere on the long arm of human chromosome 13, at position 13q12.1. While this gene does not map to the primary locus that has been identified for ARPKD in humans, it may represent a candidate gene for other recessive renal disorders that have yet to be mapped.
Hum Mol Genet 1995 Apr
PMID:Characterization of the human homologue of the mouse Tg737 candidate polycystic kidney disease gene. 763 4

The complete genomic sequence of the gene responsible for the predominant form of polycystic kidney disease, PKD1, was determined to provide a framework for understanding the biology and evolution of the gene, and to aid in the development of molecular diagnostics. The DNA sequence of a 54 kb interval immediately upstream of the poly(A) addition signal sequence of the PKD1 transcript was determined, and then analyzed using computer methods. A leucine-rich repeat (LRR) motif was identified within the resulting predicted protein sequence of the PKD1 gene. By analogy with other LRR-containing proteins, this may explain some of the disease-related renal alterations such as mislocalization of membrane protein constituents and changes in the extracellular matrix organization. Finally, comparison of the genomic sequence and the published partial cDNA sequence showed several differences between the two sequences. The most significant difference detected predicts a novel carboxy-terminus for the PKD1 gene product.
Hum Mol Genet 1995 Apr
PMID:Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat. The American PKD1 Consortium (APKD1 Consortium). 763 6

Polycystic kidney disease (PKD) is characterized by multiple renal cysts, which ultimately result in renal failure. We have reported the identification of a new gene, Ke 6, within the major histocompatibility complex, which is downregulated in two different mouse models of heritable PKD (N. Aziz, M. Maxwell, B. St.-Jacques, and B.M. Brenner. Mol. Cell. Biol. 13: 1847-1853, 1993). The Ke 6 gene gives rise to two transcripts, Ke 6a and Ke 6b. Ke 6a protein has significant homology to several mammalian and bacterial steroid dehydrogenases. The homology of Ke 6a protein to specific functional domains of the human and rat 11 beta-hydroxysteroid dehydrogenase enzyme (11 beta-HSD), which inactivates glucocorticoids, is substantial. We report here that the Ke 6 gene and the 11 beta-HSD gene are regulated in the same aberrant pattern in the cpk mouse. The strong evidence for a critical role of steroids in cystogenesis leads us to propose that a possible elevation of intrahepatic and intrarenal steroid levels occurs in the cpk mouse as a result of repression of steroid metabolic enzymes, which ultimately leads to development of cysts.
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PMID:Coordinate regulation of 11 beta-HSD and Ke 6 genes in cpk mouse: implications for steroid metabolic defect in PKD. 797 82

Polycystic kidney disease (PKD) is characterized by progressive enlargement of the kidneys due to numerous expanding cysts ultimately leading to renal failure. We have identified a gene, Ke 6, located within the H-2K/tw5 region on mouse chromosome 17, which is downregulated in two distinct murine models of heritable PKD. Ke 6 is a member of the short-chain alcohol dehydrogenase family and possess remarkable amino acid sequence conservation with several bacterial proteins with oxidoreductase function. The Ke 6 gene gives rise to two transcripts--a 1-kb Ke 6a mRNA which is abundant in kidney and liver tissue and a 1.4-kb Ke 6b mRNA which is found at a moderate level in spleen tissue. We report here the complete nucleotide sequence of Ke 6a cDNA and the expression of the Ke 6 gene in murine models of PKD. The Ke 6 gene may be intimately involved in the manifestation of these cystic kidney diseases.
Mol Cell Biol 1993 Mar
PMID:Downregulation of Ke 6, a novel gene encoded within the major histocompatibility complex, in murine polycystic kidney disease. 844 17


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