Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MTG8 is a counterpart gene of AML1 in acute myeloid leukemia with t(8:21) translocation. Most of the coding region of the MTG8 is fused with AML1 runt domain. In normal tissues, the MTG8 is highly expressed in brain, but not in hematopoietic tissues. MTG8 may be important in leukemogenesis as well as in AML1 truncation. The function of MTG8 is assumed to be as a transcription factor, because it possesses several features common to transcription factors; putative zinc finger motifs, serine/threonine/proline-rich sequences and a region similar to TAF110. In this paper, we report on the protein properties of the MTG8.
Leukemia 1997 Apr
PMID:Significance of MTG8 in leukemogenesis. 920 71

Mammalian D-type cyclins are differentially expressed during the first gap phase (G1) of the cell cycle in various cell types, and function as regulatory subunits of cyclin-dependent kinases (cdks), cdk4 and cdk6, to form holoenzymes whose activities are both necessary and rate limiting for G1 progression. Mitogenic signals induce the expression of cyclin D and cdk4 proteins, and facilitate their assembly into holoenzymes and their post-translational modification, while anti-proliferative stimuli extinguish the activity of cyclin D-dependent kinases by inducing cdk inhibitors which directly interfere with their catalytic functions and/or inhibit the post-translational activation of cyclin-bound cdks. Therefore, a variety of extracellular signals target and regulate the cyclin D/cdk4 serine/threonine kinases, which execute their critical functions during middle to late G1 phase by phosphorylating key substrates, including the retinoblastoma tumor suppressor gene products (pRb). Although overexpression of cyclin D, or inactivation of Rb or cdk inhibitor gene alone is not sufficient for cell transformation, high frequency of alterations of these genes in cancers suggests that inactivation of this particular pathway is involved in tumor development.
Leukemia 1997 Apr
PMID:Control of G1 progression by D-type cyclins: key event for cell proliferation. 920 86

Inhibitory proteins for Cdks (CKIs) are involved in cell cycle arrest induced by anti-mitotic factors, chemicals, or DNA damage in mammalian cells. High cell density also induces cell cycle arrest with unreplicated genomic DNA even in the presence of mitotic dose of the growth factors, termed contact inhibition. Although rat fibroblast cell line, 3Y1, arrested in quiescence by contact inhibition, Cdk4 bound its regulatory subunit, cyclin D1 or D3. However, these complexes were enzymatically inactive. Phosphorylation of the cyclin D1-bound Cdk4 by Cdk4-activating kinase, composed of cyclin H and MO15 (alias Cdk7), which was reconstituted in Spodoptera frugiperda cells (Sf9) could convert inactive cyclin D1-Cdk4 complex into active form in vitro, suggesting that threonine 172 in the Cdk4, whose phosphorylation is required for its activation, was in part unphosphorylated in the contact-inhibited 3Y1. Although MO15 was active in cell extracts prepared from the contact-inhibited 3Y1, activation of bacterially produced Cdk4 in the cell extracts was inhibited. Removing p27kip1 from the cell extracts allowed MO15 holoenzyme to phosphorylate the Cdk4 and to activate it, indicating that an access of MO15 to Cdk4 was inhibited by p27kip1 in the contact-inhibited 3Y1.
Leukemia 1997 Apr
PMID:Contact inhibition-induced inactivation of the cyclin D-dependent kinase in rat fibroblast cell line, 3Y1. 920 90

One of the most common chromosomal abnormalities in acute leukemia is a reciprocal translocation involving the HRX gene at chromosome locus 11q23, resulting in HRX fusion proteins. Using the yeast two-hybrid system, in vitro binding studies, and human cell culture coimmunoprecipitation experiments, we show here that a region of the HRX protein that is consistently retained in HRX leukemic fusion proteins interacts directly with SET, another protein implicated in leukemia. We have identified the binding sites on HRX for SET and show that these sequences are clustered near the A.T hooks that have been shown to bind DNA. We also show that carboxyl-terminal SET sequences, possibly the acidic tail of SET, bind to HRX. We have also found serine/threonine-specific protein phosphatase activity in anti-HRX coimmunoprecipitates. Using the phosphatase inhibitor okadaic acid and Western blotting, the phosphatase was identified as protein phosphatase 2A (PP2A). Mutation of a single amino acid in one of the SET binding sites of HRX resulted in lower amounts of both coimmunoprecipitated SET protein and coimmunoprecipitated PP2A. These results suggest that the leukemogenic effects of HRX fusion proteins may be related to interactions with SET and PP2A.
 ...
PMID:HRX leukemic fusion proteins form a heterocomplex with the leukemia-associated protein SET and protein phosphatase 2A. 935 99

Fusion peptides are hydrophobic sequences located at the N terminus of the transmembrane (TM) envelope proteins of the orthomyxoviruses and paramyxoviruses and several retroviruses. The Moloney murine leukemia virus TM envelope protein, p15E, contains a hydrophobic stretch of amino acids at its N terminus followed by a region rich in glycine and threonine residues. A series of single amino acid substitutions were introduced into this region, and the resulting proteins were examined for their abilities to be properly processed and transported to the cell surface and to induce syncytia in cells expressing the ecotropic receptor. One substitution in the hydrophobic core and several substitutions in the glycine/threonine-rich region that prevented both cell-cell fusion and the transduction of NIH 3T3 cells when incorporated into retroviral vector particles were identified. In addition, one mutation that enhanced the fusogenicity of the resulting envelope protein was identified. The fusion-defective mutants trans dominantly interfered with the ability of the wild-type envelope protein to cause syncytium formation in a cell-cell fusion assay, although no trans-dominant inhibition of transduction was observed. Certain substitutions in the hydrophobic core that prevented envelope protein processing were also found. These data indicate that the N-terminal region of p15E is important both for viral fusion and for the correct processing and cell surface expression of the viral envelope protein.
 ...
PMID:Mutational analysis of the fusion peptide of Moloney murine leukemia virus transmembrane protein p15E. 944 69

Raf-1, A-Raf and B-Raf comprise a small family of highly conserved serine/threonine protein kinases, whose activities play a fundamental role in the control of proliferation and differentiation. The best studied family member, Raf-1, is expressed ubiquitously and constitutively, and its activity is regulated by post-translational mechanisms. Raf-1 can be activated by many signals that include growth factors, tumor promoters, inflammatory cytokines, calcium mobilization, DNA damaging agents, and oxygen radicals. Ras-mediated translocation of Raf-1 to the plasma membrane is a crucial step in its activation process, and is thought to facilitate phosphorylation by membrane-bound kinases. Raf-1 has also been reported to undergo intracellular redistribution following its activation: to the perinuclear space in murine NIH3T3 cells and rat hepatic Ito cells, and into the nucleus in gerbil hippocampal pyramidal cells and human MO7 leukemia cells. In contrast to the translocation to the plasma membrane, the perinuclear and/or nuclear translocation of Raf-1 has not been investigated in detail. In this paper, we report an examination of the subcellular localization of endogenous Raf-1 in a fibroblastic cell line (Rat-1) commonly used in transformation assays. Using the methods of cellular fractionation as well as in situ immunofluorescence, we show that no detectable movement of Raf-1 to the perinuclear or nuclear space can be observed. Tethering of activated Raf to the plasma membrane does not interfere with its transforming activity.
 ...
PMID:Studies of perinuclear and nuclear translocation of the Raf-1 protein in rodent fibroblasts. 955 Oct 81

FcepsilonRI-mediated exocytosis of preformed mediators from mast cells and basophils (e.g. histamine, serotonin, beta-hexosaminidase) is sensitive to the immunosuppressants cyclosporin A and FK506 (IC50 200 and 4 nM, respectively) but not rapamycin. The mechanism of inhibition does not appear to involve tyrosine phosphorylation, hydrolysis of inositol phosphates or calcium flux. Here we report experiments using a molecular approach to assess the role of calcineurin, a serine/threonine phosphatase thought to be the primary pharmacological target of these drugs. Calcineurin's activity requires association of its catalytic (A) subunit with an intrinsic regulatory (B) subunit. We hypothesized that calcineurin-sensitive signalling events should be affected by the depletion of calcineurin B subunits, thereby reducing the number of active A:B complexes. We therefore transfected rat basophilic leukemia (RBL) cells with an inhibitory (dominant negative) form of the calcineurin A subunit, which binds the calcineurin B subunit with high affinity but does not possess catalytic activity (B subunit knock-out, BKO). In these transfected cells, the dose-response curve for the inhibition of FcepsilonRI-mediated exocytosis by FK506 was shifted to the left, indicating an increased drug sensitivity of BKO-transfected cells. We conclude that FK506 inhibition of FcepsilonRI-mediated exocytosis in mast cells specifically targets calcineurin activity.
 ...
PMID:Direct evidence that FK506 inhibition of FcepsilonRI-mediated exocytosis from RBL mast cells involves calcineurin. 968 77

The c-myb oncogene has been a target of retroviral insertional mutagenesis in murine monocytic leukemias. One mechanism by which c-myb can be activated is through the integration of a retroviral provirus into the central portion of the locus, causing premature termination of c-myb transcription and translation. We had previously shown that a leukemia-specific c-Myb protein, truncated at the site of proviral integration by 248 amino acids, had approximately a fourfold-increased half-life compared to the normal c-Myb protein, due to its ability to escape rapid degradation by the ubiquitin-26S proteasome pathway. Here we provide evidence for the existence of more than one instability determinant in the carboxy-terminal region of the wild-type protein, which appear to act independently of each other. The data were derived from examination of premature termination mutants and deletion mutants of the normal protein, as well as analysis of another carboxy-terminally truncated protein expressed in leukemia. Evidence is provided that one instability determinant is located in the terminal 87 amino acids of the protein and another is located in the vicinity of the internal region that has leucine zipper homology. In leukemias, different degrees of protein stability are attained following proviral integration depending upon how many determinants are removed. Interestingly, although PEST sequences (rich in proline, glutamine, serine, and threonine), often associated with degradation, are found in c-Myb, deletion of PEST-containing regions had no effect on protein turnover. This study provides further insight into how inappropriate expression of c-Myb may contribute to leukemogenesis. In addition, it will facilitate further studies aimed at characterizing the specific role of individual regions of the normal protein in targeting to the 26S proteasome.
 ...
PMID:Identification of protein instability determinants in the carboxy-terminal region of c-Myb removed as a result of retroviral integration in murine monocytic leukemias. 997 84

6-[3-(1-Adamantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) is a novel retinoid which induces apoptosis in the retinoic acid-resistant HL-60R human leukemia cell line. CD437-mediated poly(ADP-ribose) polymerase (PARP) cleavage and apoptosis of HL-60R cells does not require gene transcription or protein synthesis since it occurs in the presence or absence of either actinomycin D or cycloheximide. Marked activation of both the p38 and the JNK/SAPK serine and threonine kinases occurs at 1 h of exposure to CD437 with subsequent PARP cleavage at 2 h and apoptosis noted at 4 to 6 h. CD437 concentrations as little as 10 nM result in p38 activation and apoptosis of HL-60R cells. However, inhibition of p38 activation utilizing the specific inhibitor SB203580 does not block CD437-mediated PARP cleavage or apoptosis. In addition, p38 activation is dependent upon the activation of the caspase system since p38 activation is blocked by the pan ICE inhibitor Z-VAD fmk, which also inhibits CD437-mediated apoptosis and PARP cleavage in these cells. CD437-mediated activation of JNK/SAPK is not inhibited by Z-VAD fmk, suggesting that it lies upstream of CD437 activation of caspase activity and subsequent apoptosis. The role of JNK/SAPK activation in CD437-mediated apoptosis remains to be defined.
 ...
PMID:Activation of the p38 and JNK/SAPK mitogen-activated protein kinase pathways during apoptosis is mediated by a novel retinoid. 1004 65

The Chinese hamster cell lines E36 and CHOK1 dramatically differ in susceptibility to amphotropic murine leukemia virus (A-MuLV) and gibbon ape leukemia virus (GALV); E36 cells are highly susceptible to both viruses, CHOK1 cells are not. We have previously shown that GALV can infect E36 cells by using both its own receptor, HaPit1, and the A-MuLV receptor, HaPit2. Given that the two cell lines are from the same species, the loss of function of both of these receptors in CHOK1 cells is surprising. Other studies have shown that CHOK1 cells secrete proteins that block A-MuLV entry into CHOK1 as well as E36, suggesting the two A-MuLV receptors are functionally identical. However, CHOK1 conditioned medium does not block GALV entry into E36, indicating the secreted inhibitors do not block HaPit1. HaPit1 and ChoPit1 therefore differ as receptors for GALV; ChoPit1 is either inactivated by secreted factors or intrinsically nonfunctional. To determine why GALV cannot infect CHOK1, we cloned and sequenced ChoPit1 and ChoPit2. ChoPit2 is almost identical to HaPit2, which explains why CHOK1 conditioned medium blocks A-MuLV entry via both receptors. Although ChoPit1 and HaPit1 are 91% identical, a notable difference is at position 550 in the fourth extracellular region, shown by several studies to be crucial for GALV infection. Pit1 and HaPit1 have aspartate at 550, whereas ChoPit1 has threonine at this position. We assessed the significance of this difference for GALV infection by replacing the aspartate 550 in Pit1 with threonine. This single substitution rendered Pit1 nonfunctional for GALV and suggests that threonine at 550 inactivates ChoPit1 as a GALV receptor. Whether native ChoPit1 functions for GALV was determined by interference assays using Lec8, a glycosylation-deficient derivative of CHOK1 that is susceptible to both viruses and that has the same receptors as CHOK1. Unlike with E36, GALV and A-MuLV exhibited reciprocal interference when infecting Lec8, suggesting that they use the same receptor. We conclude both viruses can use ChoPit2 in the absence of the inhibitors secreted by CHOK1 and ChoPit1 is nonfunctional.
 ...
PMID:Gibbon ape leukemia virus receptor functions of type III phosphate transporters from CHOK1 cells are disrupted by two distinct mechanisms. 1007 40


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