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

We have examined clones of human malignant lymphoid cells for markers that correlate with glucocorticoid-mediated cell lysis. In glucocorticoid-sensitive clones of CEM, a human T-cell lymphoblastic leukemia line, two genes correlate with glucocorticoid-induced cell lysis. The glucocorticoid receptor (GR) itself is induced by standard glucocorticoids in sensitive clones and not in insensitive clones. The phenylpyrazolo-glucocorticoid cortivazol (CVZ) is capable of lysing several clones resistant to high concentrations of standard potent glucocorticoids. When these clones were tested for cortivazol responses, they were not only lysed by cortivazol but also showed induction of GR mRNA. Thus receptor induction appears to correlate with the lysis function of receptor in these cells. To determine what parts of the GR are required for lysis, we have mapped this function by transfecting and expressing GR and GR fragment genes in a GR-deficient CEM clone. Our results indicate that none of the known trans-activation regions of the GR are required. Removal of the steroid binding domain gives a fragment that is fully constitutive. Only one and one-half "Zn fingers" of the DNA binding region are required. We also find in CEM cells rapid suppression of the c-myc protooncogene, preceding growth arrest and cell lysis by glucocorticoids. This occurs only in clones possessing both intact receptors and lysis function. Thus the simple presence of GR alone is not sufficient to guarantee c-myc down-regulation. Introduction into the cells of c-myc driven by a promoter that does not permit suppression by glucocorticoids confers resistance to steroids. Furthermore, suppression of c-myc by antisense oligonucleotides also kills the cells. Therefore, c-myc appears to be a pivotal gene related both to ability of steroid to kill and to cell viability.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Glucocorticoids in malignant lymphoid cells: gene regulation and the minimum receptor fragment for lysis. 131 75

An alkaline unwinding assay was used to quantitate the induction of DNA strand breaks (DNA SB) in the livers of rats and mice treated in vivo, in rodent hepatocytes in primary culture, and in CCRF-CEM cells, a human lymphoblastic leukemia cell line, following treatment with tri- (TCA), di- (DCA), and mono- (MCA) chloroacetic acid and their corresponding aldehydes, tri- (chloral hydrate, CH), di- (DCAA) and mono- (CAA) chloroacetaldehyde. None of the chloroacetic acids induced DNA SB in the livers of rats at 4 hr following a single administration of 1-10 mmole/kg. TCA (10 mmole/kg) and DCA (5 and 10 mmole/kg) did produce a small amount of strand breakage in mice (7% at 4 hr) but not at 1 hr. N-nitrosodiethylamine (DENA), an established alkylating agent and a rodent hepatocarcinogen, produced DNA SB in the livers of both species. TCA, DCA, and MCA also failed to induce DNA strand breaks in splenocytes and epithelial cells derived from the stomach and duodenum of mice treated in vivo. None of the three chloroacetaldehydes induced DNA SB in either mouse or rat liver. The continuous exposure of mice to 5 g/L DCA in the drinking water for 7 and 14 days did not induce appreciable hepatic DNA SB (< 10% at 14 days), although peroxisome proliferation, as evidenced by an increased cyanide-insensitive palmitoyl CoA oxidase (PCO) activity, was stimulated to 490% (7 days) and 652% (14 days) of control. Under this protocol, DENA (0.1 g/L) produced DNA damage after both 7 days (73% of control) and 14 days (57% of control). Similarly, long-term exposure of rats (30 weeks) to 2 g/L DCA in the drinking water, a level that increased PCO activity to 364% of the control value, exhibited no DNA damage. Both the chloroacetic acids and the chloroacetaldehydes were ineffective in inducing DNA SB in cultured rat and mouse hepatocytes at concentrations below those that yielded cytotoxicity. The chloroacetic acids were also ineffective in the CCRF-CEM cells. However, two of the chloroaldehydes, DCAA and CAA, did induce DNA SB in the CCRF-CEM cells at concentrations that did not decrease the cell viability after 2 hr of treatment. Prior incubation of DCAA and CAA with a rat S9 liver homogenate eliminated much of the DNA damaging activity. These studies provide further evidence that the chloroacetic acids lack genotoxic activity not only in rodent liver, a tissue in that they induce tumors, but in a variety of other roden tissues and cultured cell types.(ABSTRACT TRUNCATED AT 400 WORDS)
Environ Mol Mutagen 1992
PMID:Analysis of DNA strand breaks induced in rodent liver in vivo, hepatocytes in primary culture, and a human cell line by chlorinated acetic acids and chlorinated acetaldehydes. 133 May 47

Interleukin-1 (IL-1) is known to synergize with phorbol esters in the induction of interleukin-2 (IL-2) expression in T-lymphoid leukemia cells and proliferation of mouse thymocytes. We used a plasmid construct containing the bacterial gene for chloramphenicol acetyltransferase under the control of the human IL-2 promoter to study the nature of this synergism in the murine thymoma cell line EL4. Although IL-1 induction of the IL-2 promoter in these cells required costimulus with phorbol myristate acetate, the signal induced by IL-1 was qualitatively different. We provide evidence to support the hypothesis that the phorbol ester signal is mediated by protein kinase C, and we show that the IL-1 signal is not. That IL-1 and phorbol myristate acetate represent different stimuli was shown by their response to protein kinase C inhibitors, capacity to synergize with increased intracellular free calcium, and requirement for protein synthesis. In addition we show that pretreatment with IL-1 can prime EL4 cells to subsequent activation by concentrations of phorbol esters not normally sufficient to induce IL-2 expression. Pretreated cells remained primed for at least 40 h after removal of the IL-1. Neither phorbol myristate acetate nor a calcium ionophore was capable of preactivating EL4 cells.
Mol Cell Biol 1990 Jun
PMID:A role for protein kinase C activity in interleukin-1 (IL-1) induction of IL-2 gene expression but not in IL-1 signal transduction. 169 59

We analyzed the genomic structure and mRNA of the RB and p53 genes in four mouse lymphoid leukemia cell lines (DL-1, DL-5, DL-8, and DL-12). Although no gross structural alteration of the RB gene was observed in any cell line, abnormalities of RB mRNA were detected in at least two cell lines. RB mRNA expression was greatly reduced in DL-12. In addition, cloning and sequencing analysis of the RB cDNA revealed that the RB mRNA in DL-8 had a 276-nucleotide deletion presumably consisting of exons 10, 11, and 12, suggesting that altered splicing resulted in the loss of these exons. Analysis of the p53 gene indicated that DL-5 had a deletion in both alleles and expressed a smaller mRNA. These results suggest that mutations of the RB or p53 genes, or both, are associated with lymphoid leukemogenesis in mice.
Mol Carcinog 1991
PMID:Identification of RB and p53 mutations in mouse lymphoma cell lines. 191 Apr 80

Cells of the hemopoietic system arise by proliferation and differentiation of progenitor cells. This process begins with multipotential stem cells which can self-renew and also undergo progressive differentiation to progenitor cells committed to particular lineages, ultimately yielding mature blood cells (D. Metcalf and M. A. S. Moore, Haematopoietic Cells, 1971). Early commitment of lymphoid progenitors is generally believed to separate the lymphoid lineage from the myeloid and erythroid lineages, whose progenitors are separated late in differentiation (Metcalf and Moore, 1971). We recently developed a derivative of Moloney murine leukemia virus (M-MuLV) in which the enhancer sequences from simian virus 40 were substituted into the M-MuLV long terminal repeat. This recombinant virus (delta Mo + SV M-MuLV) induces pre-B and B lymphoid leukemia with long latency after inoculation of 2-day-old NIH Swiss mice (R. Hanecak, P. K. Pattengale, and H. Fan, J. Virol. 62:2427-2436, 1988). In this report, we describe the derivation of a permanent, virus-producing cell line with the phenotypic characteristics of mature macrophages from a B-cell-derived lymphoblastic lymphoma induced by delta Mo + SV M-MuLV. Comparison studies of immunoglobulin heavy-chain gene rearrangements and also delta Mo + SV M-MuLV proviral integration sites confirmed that the macrophage cell line was derived from the original B-lymphoblastic lymphoma. Moreover, inoculation of the macrophage cell line into animals resulted in histiocytic sarcomas of the macrophage type, thus reflecting stable conversion of B-lymphoid tumor cells to the macrophage phenotype. These results suggest a closer relationship between lymphoid and myeloid cells than previously believed.
Mol Cell Biol 1989 May
PMID:Differentiation in vitro of a leukemia virus-induced B-cell lymphoma into macrophages. 254 61

The P388 lymphocytic leukemia and the L1210 lymphoid leukemia are used as test systems for putative cytotoxic drugs. These leukemias are also used to investigate the perturbation of cell cycle progression of various chemical compounds in more detail. There is little information on the normal growth kinetics in vivo of these leukemias. In the present report we therefore present the results from growth kinetic studies of P388 and L1210 leukemic cells growing in ascites form in mice. We used 3H-TdR autoradiography, DNA flow cytometry and the stathmokinetic method. During exponential growth both leukemias showed a growth fraction of unity. Whereas no significant cell loss was observed during the early growth phase of P388 cells, cell loss was indicated by a discrepancy between potential and actual doubling times during exponential growth of L1210 cells. During the phase of growth retardation, the proportion of G1 and G2 cells increased at the expence of a reduced S phase fraction in the P388 leukemia, whereas only small changes in cell cycle distributions were seen with time after inoculation of L1210 cells. An increasing discrepancy in the reduction of the S phase fraction and the 3H-TdRLI was seen in the P388 cells with time after inoculation. Thus, a majority of P388 cells with S phase DNA content were unlabelled during the late phase of growth restriction, indicating resting cells in S phase. A good correlation was found between the 3H-TdR LI and S phase fraction throughout the life history of L1210 cells, revealing considerable differences in in vivo growth kinetics between the two leukemias. Such differences should be considered when evaluating test results.
Virchows Arch B Cell Pathol Incl Mol Pathol 1988
PMID:In vivo growth kinetics of P388 and L1210 leukemias. 289 40

Friend-MCF virus induces erythroid leukemia when injected into newborn NFS mice whereas Moloney virus induces T-cell lymphoma. To identify the portion of Friend-MCF virus responsible for erythroid leukemia induction four in vitro recombinant viruses were constructed in which env regions or U3 regions of LTR were reciprocally exchanged between Friend-MCF and Moloney viruses. A FrMCF-Mol (LTR) virus whose genome was derived primarily from Friend-MCF virus together with 621 nucleotides of Moloney virus at its 3' end including the U3 region of LTR was a thymic lymphoma-inducing virus. A Mol-FrMCF (LTR) virus with the genome derived primarily from Moloney virus but 596 nucleotides of Friend-MCF virus information at the same region as FrMCF-Mol (LTR) was an erythroid leukemia-inducing virus. A Mol-FrMCF (env) virus whose genome was derived primarily from Moloney virus but which had 2.3 kbp of Friend MCF at the 3' end of the pol gene including most of the env gene with all of gp70 and the N terminal of p15E was a lymphoid leukemia-inducing mink cell focus-inducing virus. FrMCF-Mol (env) virus whose genome was derived primarily from Friend-MCF virus but had 2.7 kbp of Moloney virus at the same region as Mol-FrMCF (env) virus was an erythroid leukemia-inducing ecotropic virus. The Mol-FrMCF (LTR) and Mol-FrMCF (env) viruses induced mixed leukemia of erythroid and lymphoid cells in some mice.
 ...
PMID:Long terminal repeat of Friend-MCF virus contains the sequence responsible for erythroid leukemia. 385 71

A monoclonal antibody, LAU-A1, which selectively reacts with all cells of the T-lineage, was derived from a fusion between spleen cells of a mouse immunized with paediatric thymocytes and mouse myeloma P X 63/Ag8 cells. As shown by an antibody-binding radioimmunoassay and analysis by flow microfluorometry of cells labelled by indirect immunofluorescence, the LAU-A1 antibody reacted with all six T-cell lines but not with any of the B-cell lines or myeloid cell lines tested from a panel of 17 human hematopoietic cell lines. The LAU-A1 antibody was also shown to react with the majority of thymocytes and E-rosette-enriched peripheral blood lymphocytes. Among the malignant cell populations tested, the blasts from all 20 patients with acute T-cell lymphoblastic leukemia (T-ALL) were found to react with the LAU-A1 antibody, whereas blasts from 85 patients with common ALL and 63 patients with acute myeloid leukemias were entirely negative. Examination of frozen tissue sections from fetal and adult thymuses stained by an indirect immunoperoxidase method revealed that cells expressing the LAU-A1 antigen were localized in both the cortex and the medulla. From the very broad reactivity spectrum of LAU-A1 antibody, we conclude that this antibody is directed against a T-cell antigen expressed throughout the T-cell differentiation lineage. SDS-PAGE analysis of immunoprecipitates formed by LAU-A1 antibody with detergent lysates of radiolabeled T-cells showed that the LAU-A1 antigen had an apparent mol. wt of 76,000 under non-reducing conditions. Under reducing conditions a single band with an apparent mol. wt of 40,000 was observed. Two-dimensional SDS-PAGE analysis confirmed that the 76,000 mol. wt component consisted of an S-S-linked dimeric complex. The surface membrane expression of LAU-A1 antigen on HSB-2 T-cells was modulated when these cells were cultured in the presence of LAU-A1 antibody. Re-expression of LAU-A1 antigen occurred within 24 hr after transfer of the modulated cells into antibody-free medium.
Mol Immunol 1984 Oct
PMID:Monoclonal antibody against a "Pan-T-cell" antigen expressed by thymocytes, peripheral T-lymphocytes and T-cell leukemias. 643 96

Hybrid transcription factors, resulting from gene fusions in the wake of chromosomal translocations, have been implicated in leukemogenesis, but their precise contributions to oncogenic conversion remain unclear. The E2A-HLF fusion gene, formed by a t(17;19)(q22;p13) in childhood pro-B-cell acute lymphoid leukemia, encodes a hybrid protein that contains the trans-activation domain of E2A (E12/E47) linked to the bZIP DNA-binding and dimerization domain of hepatic leukemia factor (HLF). Here we report that both HLF and E2A-HLF bind to a 10-bp consensus sequence, 5'-GTTACGTAAT-3', with a core dyad-symmetric motif characteristic of the bZIP scissors-grip model of DNA binding. A probe containing this sequence bound chimeric E2A-HLF proteins in nuclear extracts of a leukemic cell line (UOC-B1) containing the t(17;19), as demonstrated by complexes supershifted with antibodies specific for amino-terminal epitopes of E2A or carboxyl-terminal eptiopes of HLF. E2A-HLF functioned as a potent trans activator of reporter gene expression from a plasmid that contained the consensus DNA-binding sequence. Interestingly, wild-type HLF was restricted in its capacity to act as a trans activator, functioning in human fetal kidney cells but not HepG2 hepatocarcinoma cells or NIH 3T3 mouse fibroblasts. The ability of the E2A-HLF hybrid protein to bind DNA in a sequence-specific manner and trans activate the expression of artificial reporter genes suggests that it could subvert transcriptional programs that normally control the growth, differentiation, and survival of lymphoid progenitor cells.
Mol Cell Biol 1994 May
PMID:DNA-binding specificity and trans-activating potential of the leukemia-associated E2A-hepatic leukemia factor fusion protein. 816 88

The gene for the human interleukin-2 receptor alpha chain (IL-2R alpha) is expressed only in stimulated, not in resting, human T lymphocytes. This gene, in conjunction with others, plays a pivotal role in eliciting the T cell-mediated immune response. We have investigated the promoter and exon 1 region, the nucleotide -300 to +300 region of this gene relative to the position of transcriptional initiation at nucleotide +1, particularly with respect to the extent of DNA methylation at the 5'-CG-3' sequences and its changes upon induction. By using RNA transfer analyses and the in vivo footprinting technique, we have confirmed the previously reported finding that, upon stimulation of lymphocytes by phytohemagglutinin (PHA) plus interleukin-2 (IL-2), the IL-2R alpha gene can be induced to be transcribed. The region of the IL-2R alpha gene analyzed for 5'-CG-3' methylation by the genomic sequencing method or a polymerase chain reaction-based method subsequent to HpaII or HhaI cleavage of the DNA does not seem to be significantly methylated in most cell types tested, except for the cytidine residue in position +198 which is partly methylated. In the DNA of cells from a chronic B cell lymphatic leukemia 5'-CCGG-3' sequences in the exon 1 region are almost completely unmethylated. These results suggest that the promoter of a gene that is crucial in promoting the immune response and may have to be activated momentarily, will not be silenced by a long-term mechanism like DNA methylation. It is striking that the absence of DNA methylation in this promoter and exon 1 segment also extends to cell types not directly associated with the immune response and even to continuous cell lines.
Hum Mol Genet 1993 Jul
PMID:The state of DNA methylation in the promoter and exon 1 regions of the human gene for the interleukin-2 receptor alpha chain (IL-2R alpha) in various cell types. 836 83


1 2 3 4 5 6 7 8 9 10 Next >>