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:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wsh is a mutant allele at the W (c-kit) locus of mice, but no significant abnormalities are found at the coding region of the Wsh allele. Since cultured mast cells derived from the spleen of Wsh/Wsh mice do not express messenger RNA (mRNA) of c-kit, we studied the interrelation between the number of mast cells and the magnitude of c-kit mRNA expression in the skin of Wsh/Wsh mice of various ages. The number of mast cells in the skin of Wsh/Wsh embryos of 18 days postcoitum (pc) was approximately 40% that of normal control (+/+) embryos, but the number of mast cells decreased exponentially after birth; the number dropped to 0.6% that of +/+ mice at day 150 after birth. A weak but apparent signal of c-kit mRNA was detectable in the skin of 18-day pc Wsh/Wsh embryos by RNase protection assay but not in the skin of 5-day-old Wsh/Wsh mice. The number of c-kit protein-containing cells was significantly greater in the skin of 18-day pc Wsh/Wsh embryos than in the skin of 5-day-old Wsh/Wsh mice. The abolishment of c-kit mRNA expression appeared to be specific, because the expression of mast cell carboxypeptidase A mRNA but not of c-kit mRNA was detectable by in situ hybridization in skin mast cells of 5-day-old Wsh/Wsh mice. Taken together, the expression of c-kit mRNA was abolished first, then the content of c-kit protein dropped to undetectable levels, and then the disappearance of Wsh/Wsh mast cells themselves followed.
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PMID:C-kit gene is expressed by skin mast cells in embryos but not in puppies of Wsh/Wsh mice: age-dependent abolishment of c-kit gene expression. 751 15

Transforming growth factor beta 1 (TGF-beta 1), a product of marrow stromal cells, inhibits the proliferation and differentiation of hematopoietic progenitor cells within the hematopoietic microenvironment. Steel factor (SF), also a product of marrow stromal cells, is an essential positive regulator of hematopoiesis in vivo. TGF-beta 1 has been shown to repress human and murine leukemic cell and murine lin- bone marrow mononuclear cell expression of the receptor for SF (c-kit). We speculated that TGF-beta 1 might exert its inhibitory effect on hematopoiesis in part by decreasing SF/c-kit interactions. Therefore, we tested the hypothesis that TGF-beta 1 inhibits both stromal cell expression of SF and hematopoietic progenitor cell expression of c-kit. We measured stromal cell expression of SF protein and hematopoietic progenitor cell expression of membrane-bound c-kit before and after exposure to recombinant human TGF-beta 1. Both stromal cell expression of SF protein and hematopoietic progenitor cell expression of c-kit protein were inhibited 50% to 80% by TGF-beta 1. Using Northern blot and ribonuclease protection assays, we determined that TGF-beta 1 repressed stromal cell SF mRNA, but did not alter SF transcript stability. TGF-beta 1 was also found to repress c-kit mRNA in human leukemic myeloblasts as well as in normal lin- hematopoietic progenitor cells. In contrast with its effect on SF mRNA, TGF-beta 1 accelerated the degradation of c-kit mRNA. We conclude that TGF-beta 1 inhibits stromal cell production of SF by repression of SF gene transcription and represses hematopoietic progenitor cell expression of c-kit by decreasing the stability of c-kit transcripts. Taking into account the importance of SF and c-kit in maintaining steady-state hematopoiesis in vivo, the dual effect of TGF-beta 1 on both SF and c-kit gene expression is likely to be one of the major mechanisms by which TGF-beta 1 inhibits hematopoiesis in vivo.
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PMID:Transforming growth factor beta 1 inhibits expression of the gene products for steel factor and its receptor (c-kit). 753 88

Expression of the c-kit tyrosine kinase growth factor receptor has been reported in some breast tumors; however, no data exist concerning expression of its ligand, stem cell factor. The aim of this study was to determine how frequently the c-kit and stem cell factor genes were coexpressed in breast tumors and tumor-derived cell lines and to determine whether coexpression of c-kit and stem cell factor could result in growth stimulation of breast tumor cells. Expression of the c-kit and stem cell factor genes in tissue specimens and cell lines was determined using an RNase protection assay, with confirmation of c-kit protein expression by immunohistochemistry and Western blotting in tumor tissue and cell lines, respectively. Of 11 tumor specimens studied, 9 expressed variable but detectable quantities of c-kit; 7 of 13 tumor-derived cell lines also expressed c-kit. All tumor specimens and cell lines expressed detectable stem cell factor mRNA, suggesting that an autocrine growth loop could exist in the majority of breast carcinomas. To determine the biological effects of coexpression of c-kit and stem cell factor, the MCF-7 cell line, which expresses only stem cell factor, was transfected with a c-kit expression vector. Coexpression of c-kit and stem cell factor in MCF-7 cells resulted in an enhanced growth rate and cloning efficiency but not a loss of the dependence of this cell line upon estrogen. Analysis of subclones expressing different amounts of c-kit protein revealed that, although they all showed enhanced growth relative to control transfectants in serum-free medium containing IGF-1, only the highest c-kit expressor responded with additional growth to exogenous soluble stem cell factor. However, all c-kit-expressing clones, but not control clones, showed growth inhibition when exposed to a blocking anti-c-kit antibody. This blocking antibody also significantly inhibited the growth of the established ZR75-1 cell line in serum-free medium containing IGF-1. Taken together, these data suggest that coexpression of stem cell factor and c-kit could be responsible for growth deregulation in a significant number of breast carcinomas.
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PMID:Coexpression of the c-kit and stem cell factor genes in breast carcinomas. 754 33

Mutations at the murine steel (Sl) locus encoding the ligand for the c-kit receptor result in defects in gametogenesis, hematopoiesis, and melanogenesis. Steel Panda (Slpan) is an allele at the Sl locus obtained by an X-ray mutagenesis protocol. Slpan/Slpan homozygotes are mildly anemic black-eyed whites with pigmented ears and scrotum; females are sterile while males are fertile. To investigate the basis of the phenotype of the Slpan mutation, the coding region of the kit ligand (KL) in Slpan/Slpan animals was characterized and shown to be identical to that from +/+ mice. RNA expression patterns in adult Slpan/Slpan mice were investigated by RNA blot analysis and RNase protection assays. KL RNA expression was shown to be reduced in several tissues including testis, lung, and kidney, to about 60% in heterozygotes and 20% in homozygous mutant mice. Intermediate effects were seen in cerebellum and spleen, while in heart and brain no change was apparent. Therefore, the Slpan mutation affects KL RNA levels in a tissue-specific manner. Histological analysis showed that the number of oocytes in neonatal homozygotes was reduced to 20% of that in heterozygotes, and that in juvenile and adult mice ovarian follicle development was arrested at the one-layered cuboidal stage, with a few exceptions. KL production by central cords of the perinatal ovary was severely reduced as shown by immunohistochemistry. In neonatal testes of homozygotes, the germ cell number was reduced to 30% of that in heterozygotes, but meiotic spermatocytes were produced on schedule in juvenile animals. Therefore, a reduced level of KL in Slpan/Slpan ovary arrests ovarian follicle development, while a similar reduction in testes has relatively little effect on spermatogonial development.
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PMID:The murine steel panda mutation affects kit ligand expression and growth of early ovarian follicles. 768 80

The tyrosine kinase receptor c-kit and its ligand KL are required for postnatal development of germ cells, in addition to their role in primordial germ cells. To clarify their function, a detailed examination of the pattern of expression of KL in postnatal gonads was undertaken. In ovaries, the expression of KL as seen by RNA blot analysis and by RNase protection assays is relatively high at birth (P0), low from P5 to P8, and high from P12 onward. KL expression is relatively high in testes of all ages. The forms of KL RNA present in the testes suggest that from P5 onward the membrane-bound form of KL predominates, while in the ovary significant amounts of both forms are present. As observed by in situ hybridization and immunohistochemistry, in the newborn ovary KL is highly expressed in central cords whose cells contribute to the formation of central growing follicles. Expression is low in follicle cells of small growing follicles and increases to high levels in three-layered follicles during late oocyte growth. Large amounts of the ligand are found within growing oocytes. After oocyte growth ceases, expression continues only in the outer layers of multilayered follicles. In the testis, from P0 through P9, KL expression is distinct in Sertoli cells, but not in germ cells. Thereafter, the intensity of KL expression declines as the number of spermatogenic cells increases within the tubules. KL in Sertoli cells appears to be concentrated basally at the stage of the cycle of the seminiferous epithelium when it is known to interact with differentiating type A spermatogonia. These data are consistent with a role for KL in oocyte growth and in facilitating proliferation and/or differentiation of type A spermatogonia.
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PMID:The expression pattern of the c-kit ligand in gonads of mice supports a role for the c-kit receptor in oocyte growth and in proliferation of spermatogonia. 768 86

Steel factor (SF), the ligand for c-kit, is an essential regulator of normal hematopoiesis, melanogenesis, gametogenesis, and mast-cell growth and development. Hematopoietic stromal cells are important sources of SF, because inactivation of SF in mice results in defects in the support function of hematopoietic stromal cells. To identify specific cells that produce, and factors that govern the expression of the different isoforms of SF in human hematopoiesis, we quantified levels of SF mRNA and membrane-bound protein in human stromal cells before and after exposure to recombinant human interleukin (IL)-1 alpha, a cytokine known to induce the expression of a variety of hematopoietic growth factors. In addition, because stromal cells in longterm bone marrow cultures (LTBMC) are supportive of hematopoietic progenitor cell survival in vitro, while umbilical vein endothelial cells (EC) and diploid fibroblasts (DF) are not, we also sought to test the hypothesis that SF gene expression would differ in cells from LTBMC when compared with EC or DF. Using reverse-transcription polymerase chain reaction amplification (RT-PCR), ribonuclease protection assays (RPA), and Northern blot analysis, SF was found to be constitutively transcribed in EC, DF, and LTBMC. IL-1 alpha neither induced accumulation of SF mRNA nor altered the ratio of exon 6+ to exon 6- transcripts in these stromal cells. By Northern blot analysis, the predominant SF mRNA species was shown to be 5.6 kb; a minor population of 3.6 kb was also found. Low levels of membrane-bound SF protein were found to be constitutively expressed by all three types of stromal cells, and were not regulated by IL-1 alpha. We conclude that the unique capacity of LTBMC to support in vitro hematopoiesis, when compared with EC or DF, cannot be explained on the basis of qualitative or quantitative differences in SF gene expression in these cells.
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PMID:Constitutive expression of steel factor gene by human stromal cells. 768 92

Because mutations in receptor tyrosine kinases may contribute to cellular transformation, studies were undertaken to examine c-kit in human leukemia. Isoforms of c-kit have been characterized in the human megakaryoblastic leukemia cell line M-07. Deletion of the four amino acids Gly-Asn-Asn-Lys in the extracellular domain represents an alternatively spliced isoform that has been shown by others, in mice, to be associated with constitutive receptor autophosphorylation (Reith et al, EMBO J 10:2451, 1991). Additional isoforms differ in the inclusion or exclusion of a serine residue in the interkinase domain, a region that contains the binding site for phosphatidylinositol 3-kinase. By RNase protection analysis, we have shown coexpression of the Gly-Asn-Asn-Lys+ and Gly-Asn-Asn-Lys- isoforms, with dominance of the Gly-Asn-Asn-Lys- transcript, in normal human bone marrow, normal melanocytes, a range of tumor cell lines, and the blasts of 23 patients with acute myeloid leukemia. Analysis of transcripts for the Ser+ and Ser- isoforms also showed coexpression in all normal and leukemic cells examined. The ratios of isoform expression for both the Gly-Asn-Asn-Lys and Ser variants were relatively constant, providing no evidence in the tumors examined that upregulation of one isoform contributes to the neoplastic process.
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PMID:Expression of isoforms of the human receptor tyrosine kinase c-kit in leukemic cell lines and acute myeloid leukemia. 768 88

Cell surface levels of the receptor tyrosine kinase P145(c-kit), the product of the c-kit proto-oncogens, in a panel of 80 primary adult acute myeloid leukaemia (AML) specimens collected at presentation were quantitated by immunofluorescence and flow cytometry, and compared with levels on CD34+ bone marrow cells from normal donors. Receptor levels on AML blast cells were extremely variable and were similar to, or less than, those on normal stem and progenitor cells. In general P145(c-kit) expression was higher on cells of immature phenotype (FAB M1 and M2). c-kit mRNA was quantitated by ribonuclease protection assay (RPA) and was shown to be correlated with cell surface protein expression (r=0.76; P<0.001). This indicates that ligand-mediated receptor internalisation or other mechanisms of increased protein turnover are not responsible for variations in the level of P145(c-kit) in AML specimens. Quantitative Southern blotting was used to examine c-kit gene copy number in 25 of these specimens and was found to be normal in all but one. Thus we have found little evidence of over-expression of c-kit in adult AML. mRNA for the c-kit ligand, Steel Factor (SLF) was also quantitated by RPA in these specimens. While SLF message was detectable (limit of detection approximately 10(4) copies per 10 microgram total RNA; equivalent to 1 copy per 100 cells) in 19% of cases, these specimens in general contained low levels of c-kit mRNA. Thus, an autocrine cycle involving c-kit and SLF does not appear to be a common feature of AML.
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PMID:Increased expression of c-Kit or its ligand Steel Factor is not a common feature of adult acute myeloid leukaemia. 863 38

The expression of HOXB cluster genes (i.e., B1 through B9) was evaluated in purified IL-2/IL-1 beta-activated NK lymphocytes from normal adult peripheral blood by RNase protection and reverse transcription-PCR. In quiescent NK cells these genes are essentially not expressed. After IL-2/IL-1 beta addition, we observed a coordinate induction wave in the 3'-5' HOXB cluster direction, i.e., from B1 through B9. As notable exceptions, B8 is silent, while B9 RNA is detected starting from 6 h through day 11. Furthermore, the 3' located B2/B3/B4 are expressed earlier and at higher level than the 5' located B5/B6/B7/B8. In IL-2/IL-1 beta-activated NK cells, treatment with antisense oligonucleotides targeting B2 mRNA causes a significant inhibition of both cell proliferation and expression of activation markers (i.e., IL-2R alpha-chain and transferrin receptor). These studies provide novel evidence of the role of HOX genes in adult NK cell proliferation. Thus, 1) a coordinate activation of HOXB genes from the 3'-->5' cluster side apparently underlies IL-2/IL-1 beta-induced NK cell activation. 2) Since NK cell activation and survival induced by IL-12 and c-kit ligand, respectively, are not associated with cell proliferation of HOXB gene expression, it is apparent that HOXB gene induction is specifically associated with IL-2-induced NK cell proliferation. 3) Studies with antisense oligomer targeting HOXB2 mRNA suggest an important role for 82 in NK cell proliferation, possibly in part via the IL-2R.
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PMID:HOXB cluster genes in activated natural killer lymphocytes: expression from 3'-->5' cluster side and proliferative function. 880 46

Stem cell factor (SCF) is a pleiotropic growth factor that is expressed by the ovine corpus luteum throughout its life span by both small and large steroidogenic cells. Determination of the action of SCF, however, requires localization of its receptor, c-kit; therefore, the objectives of the present study were to identify and localize c-kit within corpora lutea. Two cDNAs encoding different portions of the c-kit molecule were amplified by the polymerase chain reaction. The first was a 558-base pair (bp) cDNA encoding portions of the transmembrane and tyrosine kinase domains; the second was a 632-bp cDNA encoding most of the ligand-binding domain. Expression of c-kit was quantified by RNase protection assay of total cellular RNA collected on Days 3, 7, 10, 13, and 16 (n = 4, 4, 5, 4, and 4 per group, respectively) of the estrous cycle (Day 0 = estrus). The level of c-kit mRNA was low early in the luteal phase, reached (p < 0.05) maximum levels on Day 13, and then decreased (p < 0.01) on Day 16. On Day 3 (n = 4), c-kit was expressed in a cell-specific manner throughout the corpus luteum; identity of the specific cell types expressing c-kit could not be determined at this stage. On Day 14 (n = 4), c-kit did not appear to be expressed within large luteal cells but was prominently expressed in cells that surrounded large luteal cells and that possessed the morphological characteristics of small luteal cells and endothelial cells. Given the temporal regulation of c-kit expression within the corpus luteum, these data suggest that luteal SCF may act locally.
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PMID:Ontogeny of stem cell factor receptor (c-kit) messenger ribonucleic acid in the ovine corpus luteum. 974 52


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