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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dietary intake of the essential trace element selenium (Se) regulates expression of genes for selenoproteins and certain non-Se-containing proteins. However, these proteins do not account for all of Se's biological effects. The objective of this work was to identify additional genes whose expression is regulated by Se. Identification of these genes may reveal new functions for Se or define mechanisms for its biological effects. Weanling male Sprague-Dawley rats were fed a Torula yeast-based Se-deficient basal diet or the same diet supplemented with 0.5 mg Se/kg diet as sodium selenite for 13 weeks. Total RNA was used as template for RNA fingerprinting. Two differentially expressed cDNA fragments were identified and cloned. The first had 99% nucleotide identity with rat liver estrogen sulfotransferase (EST) isoform-6. The second had 99% nucleotide sequence identity with rat liver alpha 2u-globulin. The mRNA levels for both were markedly reduced in Se deficiency. Laser densitometry showed that EST mRNA in Se deficiency was 7.3% of that in Se-adequate rat liver. The level of alpha 2u-globulin mRNA in Se-deficient rat liver was only 12.6% of that in Se-adequate rat liver. These results indicate that dietary Se may play a role in steroid hormone metabolism in rat liver.
J Steroid Biochem Mol Biol 1998 Mar
PMID:Selenium regulates gene expression for estrogen sulfotransferase and alpha 2U-globulin in rat liver. 961 24

A pulmonary Cryptococcus neoformans (Cne: strain 52D, ATCC24067) infection model in mice was used to examine the possible role for T cell-mediated immunity in regulating vascular adhesion molecules on lung endothelium during development of granulomatous inflammation. Resolution of pulmonary Cne infection in C.B-17 mice begins by Day 14 following intratracheal inoculation and depends on T cell-mediated recruitment of monocytes followed by their activation. C.B-17 scid/scid (SCID) mice mount a less exuberant pulmonary inflammatory response, recruit fewer monocytes into their lungs, and fail to clear the infection. Recruitment of leukocytes into infected tissue is mediated by both the interaction of adhesion molecules expressed on the surface of activated vascular endothelial cells with ligands on circulating cells, and the directed response of these leukocytes to chemotactic factors. The kinetics of expression of the endothelial cell adhesion molecules E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), all previously shown to regulate monocyte recruitment, were examined in the lungs of infected C.B-17 and SCID mice during pulmonary infection to determine if T cells were necessary for their upregulation. Immunohistochemical analysis showed that upregulation of E-selectin, VCAM-1, and ICAM-1 did not differ significantly between C.B-17 and SCID mice at any time during infection. Maximal expression in C.B-17 and SCID mice was noted between Days 5 and 7 for all three molecules and preceded maximal influx of leukocytes into the lung. Thus, the inability of SCID mice to recruit optimal numbers of monocytes into infected lungs was not the result of a failure to express the critical adhesion molecules early in infection, but likely reflected absence of immune dependent chemotactic factors.
Am J Respir Cell Mol Biol 1998 Oct
PMID:T and B cell independence of endothelial cell adhesion molecule expression in pulmonary granulomatous inflammation. 976 55

Cryptococcus neoformans is a fungus that is pathogenic in humans and that can produce melanin in vitro. Melanization is associated with virulence, but there is no evidence that melanin is made during infection. Melanins are difficult to study because they are amorphous and insoluble. Melanin-binding peptides from a phage display library were used to demonstrate that C. neoformans makes melanin-like compounds in tissue. Melanin-binding peptides were characterized by a high proportion of positively charged and aromatic residues. Two other methods, demonstration of an antibody response to melanin in mice infected with C. neoformans and analysis of yeast cell walls in infected tissue by light microscopy, were used to support these findings. The demonstration that C. neoformans melanizes in tissue has important implications for pathogenesis and drug discovery.
Mol Cell Biol 1999 Jan
PMID:Melanization of Cryptococcus neoformans in murine infection. 985 97

Pleural mononuclear phagocytes (PleMP) were isolated from normal rats by pleural lavage and compared with autologous peritoneal (PerMP) and bronchoalveolar mononuclear phagocytes (BAMP) isolated by peritoneal and bronchoalveolar lavage, respectively. The phagocytic activity of PleMP, PerMP, and BAMP, evaluated by testing their ability to ingest latex beads, was lower for PleMP and PerMP than for BAMP. The phenotype of PleMP, PerMP, and BAMP was characterized by immunocytochemical staining with a panel of monoclonal antibodies (mAbs). As expected, PleMP, PerMP, and BAMP did not react with OX19, OX33, ED5, MOM/3F12/F2, and anticytokeratin mAbs, specific for T lymphocytes, B lymphocytes, dendritic cells, granulocytes, and epithelial/mesothelial cells, respectively. Moreover, PleMP and PerMP populations were highly enriched with OX6-, OX42-, ED7-, and ED8-positive MP, whereas BAMP population was enriched with ED1- and ED9-positive cells. To test the ability of PleMP, PerMP, and BAMP to function as accessory cells (AC), mitomycin C-treated MP were used as stimulatory cells in mixed leukocyte reaction experiments, using allogeneic T cells as responders. 3HdTR incorporation by T cells was assessed as an index of AC function. PleMP and PerMP were more potent AC than BAMP. Moreover, when cultured together with autologous pulmonary interstitial dendritic cells, PleMP and PerMP exerted a more potent ability to stimulate T-cell proliferation than did BAMP. To investigate the capacity of MP to function as bactericidal and fungicidal cells, we tested their ability to kill Escherichia coli and Cryptococcus neoformans, respectively. PleMP and PerMP were less potent bactericidal and fungicidal cells than BAMP. The results of this study demonstrate that PleMP isolated from normal rat pleural space are functionally and phenotypically different from BAMP but similar to PerMP, and suggest that these cells might play an important role in cell-mediated immune reactions in the pleural space.
Am J Respir Cell Mol Biol 1999 Jan
PMID:Phenotypic and functional characterization of normal rat pleural macrophages in comparison with autologous peritoneal and alveolar macrophages. 987 Sep 27

Cryptococcus neoformans is a fungal pathogen that causes meningitis in patients immunocompromised by AIDS, chemotherapy, organ transplantation, or high-dose steroids. Current antifungal drug therapies are limited and suffer from toxic side effects and drug resistance. Here, we defined the targets and mechanisms of antifungal action of the immunosuppressant rapamycin in C. neoformans. In the yeast Saccharomyces cerevisiae and in T cells, rapamycin forms complexes with the FKBP12 prolyl isomerase that block cell cycle progression by inhibiting the TOR kinases. We identified the gene encoding a C. neoformans TOR1 homolog. Using a novel two-hybrid screen for rapamycin-dependent TOR-binding proteins, we identified the C. neoformans FKBP12 homolog, encoded by the FRR1 gene. Disruption of the FKBP12 gene conferred rapamycin and FK506 resistance but had no effect on growth, differentiation, or virulence of C. neoformans. Two spontaneous mutations that confer rapamycin resistance alter conserved residues on TOR1 or FKBP12 that are required for FKBP12-rapamycin-TOR1 interactions or FKBP12 stability. Two other spontaneous mutations result from insertion of novel DNA sequences into the FKBP12 gene. Our observations reveal that the antifungal activities of rapamycin and FK506 are mediated via FKBP12 and TOR homologs and that a high proportion of spontaneous mutants in C. neoformans result from insertion of novel DNA sequences, and they suggest that nonimmunosuppressive rapamycin analogs have potential as antifungal agents.
Mol Cell Biol 1999 Jun
PMID:Rapamycin antifungal action is mediated via conserved complexes with FKBP12 and TOR kinase homologs in Cryptococcus neoformans. 1033 Jan 50

Cryptococcus neoformans is an opportunistic fungal pathogen with a defined sexual cycle. The gene encoding a heterotrimeric G-protein beta subunit, GPB1, was cloned and disrupted. gpb1 mutant strains are sterile, indicating a role for this gene in mating. GPB1 plays an active role in mediating responses to pheromones in early mating steps (conjugation tube formation and cell fusion) and signals via a mitogen-activated protein (MAP) kinase cascade in both MATalpha and MATa cells. The functions of GPB1 are distinct from those of the Galpha protein GPA1, which functions in a nutrient-sensing cyclic AMP (cAMP) pathway required for mating, virulence factor induction, and virulence. gpb1 mutant strains are also defective in monokaryotic fruiting in response to nitrogen starvation. We show that MATa cells stimulate monokaryotic fruiting of MATalpha cells, possibly in response to mating pheromone, which may serve to disperse cells and spores to locate mating partners. In summary, the Gbeta subunit GPB1 and the Galpha subunit GPA1 function in distinct signaling pathways: one (GPB1) senses pheromones and regulates mating and haploid fruiting via a MAP kinase cascade, and the other (GPA1) senses nutrients and regulates mating, virulence factors, and pathogenicity via a cAMP cascade.
Mol Cell Biol 2000 Jan
PMID:The G-protein beta subunit GPB1 is required for mating and haploid fruiting in Cryptococcus neoformans. 1059 37

Cryptococcus neoformans is a basidiomycete yeast and opportunistic human pathogen of increasing clinical importance due to the increasing population of immunocompromised patients. To further investigate signal transduction cascades regulating fungal pathogenesis, we have identified the gene encoding a RAS homologue in this organism. The RAS1 gene was disrupted by transformation and homologous recombination. The resulting ras1 mutant strain was viable, but failed to grow at 37 degrees C, and exhibited significant defects in mating and agar adherence. The ras1 mutant strain was also avirulent in an animal model of cryptococcal meningitis. Reintroduction of the wild-type RAS1 gene complemented these ras1 mutant phenotypes and restored virulence in animals. A dominantly active RAS1 mutant allele, RAS1Q67L, induced a differentiation phenotype known as haploid fruiting, which involves filamentation, agar invasion and sporulation in response to nitrogen deprivation. The ras1 mutant mating defect was suppressed by overexpression of MAP kinase signalling elements and partially suppressed by exogenous cAMP. Additionally, cAMP also suppressed the agar adherence defect of the ras1 mutant. However, the ability of the ras1 mutant strain to grow at elevated temperature was not restored by cAMP or MAP kinase overexpression. Our findings support a model in which RAS1 signals in C. neoformans through cAMP-dependent, MAP kinase, and RAS-specific signalling cascades to regulate mating and filamentation, as well as growth at high temperature which is necessary for maintenance of infection.
Mol Microbiol 2000 Apr
PMID:RAS1 regulates filamentation, mating and growth at high temperature of Cryptococcus neoformans. 1079 22

Cryptococcus neoformans (= Filobasidiella neoformans) is a significant emerging fungal pathogen of humans. To understand the evolution of this pathogen, 34 strains were obtained from various locations around the world and fragments of four genes were sequenced from each. These strains represented all three varieties and five serotypes. The four sequenced genes are: (i) the mitochondrial large ribosomal subunit RNA; (ii) the internal transcribed spacer region of the nuclear rRNA, including ITS1, 5.8S rRNA subunit and ITS2; (iii) orotidine monophosphate pyrophosphorylase; and (iv) diphenol oxidase. Phylogenetic analyses indicated considerable divergence among lineages, which corresponded to the current classification of C. neoformans into three varieties. However, there is no apparent phylogeographic pattern. Significant incongruences were observed among gene genealogies. The analyses indicated that the major lineages in C. neoformans diverged tens of millions of years ago but have undergone recent dispersion and hybridization.
Mol Ecol 2000 Oct
PMID:Multiple gene genealogies reveal recent dispersion and hybridization in the human pathogenic fungus Cryptococcus neoformans. 1105 May 43

Cellular differentiation, mating, and filamentous growth are regulated in many fungi by environmental and nutritional signals. For example, in response to nitrogen limitation, diploid cells of the yeast Saccharomyces cerevisiae undergo a dimorphic transition to filamentous growth referred to as pseudohyphal differentiation. Yeast filamentous growth is regulated, in part, by two conserved signal transduction cascades: a mitogen-activated protein kinase cascade and a G-protein regulated cyclic AMP signaling pathway. Related signaling cascades play an analogous role in regulating mating and virulence in the plant fungal pathogen Ustilago maydis and the human fungal pathogens Cryptococcus neoformans and Candida albicans. We review here studies on the signaling cascades that regulate development of these and other fungi. This analysis illustrates both how the model yeast S. cerevisiae can serve as a paradigm for signaling in other organisms and also how studies in other fungi provide insights into conserved signaling pathways that operate in many divergent organisms.
Microbiol Mol Biol Rev 2000 Dec
PMID:Signal transduction cascades regulating fungal development and virulence. 1110 18

Cryptococcus neoformans is an important human pathogenic fungus with a defined sexual cycle and well-developed molecular and genetic approaches. C. neoformans is predominantly haploid and has two mating types, MATa and MATalpha. Mating is known to be regulated by nutritional limitation and thought also to be regulated by pheromones. Previously, a portion of the MATalpha locus was cloned, and a presumptive pheromone gene, MFalpha1, was identified by its ability to induce conjugation tube-like filaments when introduced by transformation into MATa cells. Here, the ability of the MFalpha1 gene to induce these morphological changes in MATa cells was used as a phenotypic assay to perform a structure-function analysis of the gene. We show that the MFalpha1 open reading frame is required for the morphological response of MATa cells. We also find that the cysteine residue of the C-terminal CAAX motif is required for activity of the MFalpha1 pheromone. In addition, we use a reporter system to measure the expression levels of the MFalpha1 pheromone gene and find that two signals, nutrient starvation and the presence of factors secreted by mating partner cells, impinge on this promoter and regulate MFalpha1 expression. We identify a second pheromone gene, MFalpha2, and show phenotypically that this gene is also expressed. Finally, we have synthesized the MFalpha1 pheromone and show that only the predicted mature modified form of the alpha-factor peptide triggers morphological responses in MATa cells.
Mol Microbiol 2000 Dec
PMID:Characterization of the MFalpha pheromone of the human fungal pathogen cryptococcus neoformans. 1112 75


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