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

The Frat1 proto-oncogene was first identified as a gene contributing to tumor progression in T-cell lymphomas induced by retroviral insertional mutagenesis with the Moloney murine leukemia virus. The biological function of Frat remained elusive until its Xenopus homologue GBP was isolated as a glycogen synthase kinase 3 (GSK3)-binding protein and was shown to be an essential component of the maternal Wnt-signaling pathway. To date two Frat homologues have been described in the mouse, Frat1 and Frat3. The proteins encoded by these two genes are 84% identical. Here we describe the cloning and characterization of a third murine Frat homologue, Frat2, which is the mouse ortholog of human FRAT2. Frat1 and Frat2 are juxtaposed on chromosome 19 in a chromosomal organization conserved between man and mouse. We show that Frat1 and Frat2 are phosphorylated, which is the first evidence that these proteins are subject to posttranslational modification. Like Frat1, Frat2 is able to bind to GSK3beta. However, a side-by-side comparison of the murine Frat proteins for their capacity to induce signaling through beta-catenin/T-cell factor reveals that Frat2 is a less potent activator of the canonical Wnt pathway. Frat2 protein accumulates to higher levels upon transfection into 293T cells than either Frat1 or Frat3. Thus, whereas Frat1 may be a core component of canonical Wnt-signaling, Frat2 might very well be part of a divergent intracellular GSK3beta pathway.
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PMID:Characterization and functional analysis of the murine Frat2 gene. 1507 80

The Wnt signaling pathways are important in many developmental events. The canonical Wnt pathway is one of the three major Wnt-mediated intracellular signaling pathways and is thought to activate Dvl followed by the stabilization of beta-catenin. In Xenopus, this pathway is involved in dorsal determination, anterior-posterior patterning during gastrulation, and neural induction. Here we describe a role for the Xenopus ELL (Eleven-nineteen Lysine-rich Leukemia) gene product in canonical Wnt signaling. Translocation of ELL has been associated with acute myeloid leukemia and the protein possesses three functional domains. We identified rELL-C from a rat brain cDNA library as a binding factor for Dishevelled (Dvl); it represents a partial sequence of rat ELL lacking the pol II elongation domain and has been shown to suppress canonical Wnt signaling. Next, we isolated two Xenopus homologs of ELL, xELL1 and xELL2. No obvious phenotypes were observed with microinjection of full-length xELL1 or xELL2 mRNA, however, microinjection with their occludin homology domain inhibited Wnt signaling at the level of Dvl and upstream of beta-catenin. Intracellular localization of microinjected xELL1- and xELL2-GFP mRNAs showed localization of the full-length products in the nucleus and the occludin-homology domain products in cytoplasm. These results raise the possibility that ELL, which is thought to function as a transcription factor in nuclei, can serve other, novel roles to suppress canonical Wnt signaling in the cytoplasm.
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PMID:Inhibition of the canonical Wnt signaling pathway in cytoplasm: a novel property of the carboxyl terminal domains of two Xenopus ELL genes. 1511 28

A novel mutagenic compound, 9-(4'-aminophenyl)-9H- pyrido[3,4-b]indole (aminophenylnorharman, APNH), is shown to be formed by the in vitro enzymatic reaction of 9H-pyrido[3,4-b]indole (norharman) and aniline. APNH generates DNA adducts (dG-C8-APNH), and is potently genotoxic to bacteria and mammalian cells. APNH has also been demonstrated to be formed in vivo from norharman and aniline, and suggested to be a new type of endogenous mutagenic compound. To determine its carcinogenic activity, long-term administration of APNH was investigated in 93 male and 90 female F344 rats. Rats were fed diets containing 0, 20 or 40 p.p.m. from 7 weeks of age. All animals were killed after 85 weeks treatment and necropsy was performed. Hepatocellular carcinomas (HCCs) were induced at incidences of 10 and 79% in male rats fed 20 and 40 p.p.m. APNH, and 34% in female rats fed 40 p.p.m. of APNH, respectively. In addition, colon adenocarcinomas were found at incidences of 3 and 9% in male rats, and 4 and 13% in female rats fed 20 and 40 p.p.m. of APNH, respectively. Other tumors, including thyroid carcinomas and mononuclear cell leukemia, were also seen in rats fed APNH. Polymerase chain reaction-single strand conformation polymorphism analysis revealed beta-catenin gene mutations in 24% of HCCs and K-ras, beta-catenin and Apc gene mutations were found in 22, 44 and 33% of colon cancers induced by APNH, respectively. Most mutations occurred at G:C base pairs. beta-Catenin protein accumulations in the nucleus and cytoplasm were also revealed in both liver and colon tumors. Thus, APNH induced liver and colon cancers with K-ras, beta-catenin and Apc gene mutations in F344 rats.
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PMID:Carcinogenicity of aminophenylnorharman, a possible novel endogenous mutagen, formed from norharman and aniline, in F344 rats. 1514 89

We recently published the construction and evaluation of a beta-catenin-dependent, highly active promoter, CTP1, and its possible application for the treatment of colorectal cancer using gene-directed enzyme prodrug therapy with adenoviral (Ad) vectors. Alternative Ad-based approaches such as tumor-specific, replication-competent vectors and/or exploiting therapeutic gene products with intrinsic toxic activity, such as gibbon ape leukemia virus fusogenic membrane glycoprotein, diphtheria toxin A (DTA), and ricin, would demand a very tightly regulated promoter to avoid breakthrough replication and toxicity in nontumor tissue and Ad producer cell lines. In this study we optimized the activity/specificity profile of the synthetic beta-catenin-dependent promoter by varying its basal promoter, the number of Tcf binding sites, and the distance between these and the basal promoter. The optimal promoter, CTP4, showed virtually undetectable expression in cells with normal beta-catenin regulation but high level expression in cells deregulated for beta-catenin. Using CTP4 we were able to generate, for the first time to our knowledge, an Ad vector expressing fully active wild-type DTA without the need for time-consuming and cumbersome production systems. CTP4 should be the promoter of choice for Ad-based gene therapies of tumors deregulated for beta-catenin. We provide preliminary evidence that these may include prostate and ovarian as well as colorectal cancer.
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PMID:Optimization of a synthetic beta-catenin-dependent promoter for tumor-specific cancer gene therapy. 1523 50

The role of beta-catenin in epithelial neoplasms has been widely studied whereas current knowledge regarding beta-catenin gene and protein expression in bone marrow cells derived from normal haematopoiesis and clonal haematological disorders is lacking. beta-Catenin gene expression was quantitatively investigated in bone marrow cells derived from clonal haematological disorders [acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML], Ph- myeloproliferative disorders, n = 96) compared with non-neoplastic haematopoiesis (n = 33) by real-time reverse transcription polymerase chain reaction. Cellular localization of beta-catenin protein was detected by immunocytochemistry. beta-Catenin gene expression was significantly increased in AML compared with ALL cases (P < 0.0001), Ph+ CML (P < 0.0001) and non-neoplastic haematopoiesis (P = 0.019). Immunocytochemistry revealed that, in non-neoplastic haematopoiesis, the granulopoietic lineage as well as megakaryocytes showed membranous and cytoplasmic staining to various degrees along with unlabelled nuclei. Besides haematopoiesis, beta-catenin prominently marked bone marrow vascularity and diverse stroma cells. beta-Catenin gene was inversely expressed in AML and ALL with a lack of protein expression in neoplastic cells in ALL. In contrast, the other haematological disorders under study, except for Ph+ CML, did not show significant alterations of overall beta-catenin gene expression compared with normal bone marrow. These data suggest different regulatory mechanisms in the expression and function of beta-catenin in haematopoietic cells.
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PMID:Aberrant expression of beta-catenin discriminates acute myeloid leukaemia from acute lymphoblastic leukaemia. 1525 3

Cancer can be viewed as a hierarchical system that is dependent on a small population of "cancer stem cells" with unlimited self-renewal potential for continued growth and propagation of tumors. The identity and nature of these cells remains enigmatic, but an improved understanding of their biology may allow for selective therapeutic targeting. A recent report by sheds new light on leukemia stem cells by identifying the cells with in vitro self-renewing properties in various phases of chronic myelogenous leukemia, and linking the self-renewal properties of this population to activation of beta-catenin, a major effector of the canonical Wnt signaling pathway.
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PMID:Blasts from the past: new lessons in stem cell biology from chronic myelogenous leukemia. 1538 May 9

beta-Catenin has been implicated in leukemic cell proliferation. We compared the effects of aspirin (ASA) and the ortho, meta, and para positional isomers of NO-donating aspirin (NO-ASA) on cell growth and beta-catenin expression in human Jurkat T leukemic cells. Cell growth inhibition was strong: IC(50) for p-, o-, and m- were 20+/-1.6 (mean+/-SEM), 15+/-1.5, and 200+/-12 microM, respectively, in contrast to that of ASA (3200+/-375 microM). The para isomer of NO-ASA degraded beta-catenin in a dose- and time-dependent manner coinciding with increasing expression of activated caspase-3. The caspase inhibitor ZVAD blocked beta-catenin cleavage by p-NO-ASA and partially reversed cell growth inhibition by p-NO-ASA but not that by ASA. A denitrated analog of p-NO-ASA did not degrade beta-catenin indicating the importance of the NO-donating moiety. Our findings suggest that NO-ASA merits further study as an agent against leukemia.
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PMID:NO-donating aspirin inhibits the growth of leukemic Jurkat cells and modulates beta-catenin expression. 1556 57

The beta-catenin protein is at the core of the canonical Wnt signalling pathway. Wnt stimulation leads to beta-catenin accumulation, nuclear translocation and interaction with T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors to regulate genes important for embryonic development and proliferation. Wnt/beta-catenin can promote stem cell self-renewal and is dysregulated in colon carcinoma. We have examined the role of the Wnt pathway in the development of acute myeloid leukaemia (AML) and find that the beta-catenin protein is readily detected in primary AML samples. Using transfection of a TCF/LEF reporter construct into primary AML cells and normal human progenitors, we find increased reporter activity in 16/25 leukaemia samples. Retrovirally mediated expression of a mutant active beta-catenin in normal progenitors preserves CD34 expression and impairs myelomonocytic differentiation. Activation of TCF/LEF signalling decreases factor withdrawal-induced apoptosis of normal progenitors. A significant proportion of AML cases show aberrant expression of components of the Wnt pathway including Wnt-1, Wnt-2b and LEF-1. These results provide evidence for the involvement of the Wnt/beta-catenin pathway in the pathogenesis of AML.
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PMID:Constitutive activation of the Wnt/beta-catenin signalling pathway in acute myeloid leukaemia. 1573 43

The heterotrimeric G protein G(12) has been implicated in such cellular regulatory processes as cytoskeletal rearrangement, cell-cell adhesion, and oncogenic transformation. Although the activated alpha-subunit of G(12) has been shown to interact directly with a number of protein effectors, the roles of many of these protein-protein interactions in G(12)-mediated cell physiology are poorly understood. To begin dissecting the specific cellular pathways engaged upon G(12) activation, we produced a series of substitution mutants in the regions of Galpha(12) predicted to play a role in effector binding. Here we report the identification and characterization of an altered form of Galpha(12) that is functionally uncoupled from signaling through the monomeric G protein Rho, a protein known to propagate several Galpha(12)-mediated signals. This mutant of Galpha(12) fails to bind the Rho-specific guanine nucleotide exchange factors p115RhoGEF and LARG (leukemia-associated RhoGEF), fails to stimulate Rho-dependent transcriptional activation, and fails to trigger activation of RhoA and the Rho-mediated cellular responses of cell rounding and c-jun N-terminal kinase activation. Importantly, this mutant of Galpha(12) retains coupling to the effector protein E-cadherin, as evidenced by its ability both to bind E-cadherin in vitro and to disrupt E-cadherin-mediated cell-cell adhesion. Furthermore, this mutant retains the ability to trigger beta-catenin release from the cytoplasmic domain of cadherin. This identification of a variant of Galpha(12) that is selectively uncoupled from one signaling pathway while retaining signaling capacity through a separate pathway will facilitate investigations into the mechanisms through which G(12) proteins mediate diverse biological responses.
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PMID:Selective uncoupling of G alpha 12 from Rho-mediated signaling. 1574 95

During spermatogenesis, extensive restructuring of cell junctions takes place in the seminiferous epithelium to facilitate germ cell movement. However, the mechanism that regulates this event remains largely unknown. Recent studies have shown that nitric oxide (NO) likely regulates tight junction (TJ) dynamics in the testis via the cGMP/protein kinase G (cGMP-dependent protein kinase, PRKG) signaling pathway. Due to the proximity of TJ and adherens junctions (AJ) in the testis, in particular at the blood-testis barrier, it is of interest to investigate if NO can affect AJ dynamics. Studies using Sertoli-germ cell cocultures in vitro have shown that the levels of NOS (nitric oxide synthase), cGMP, and PRKG were induced when anchoring junctions were being established. Using an in vivo model in which adult rats were treated with adjudin [a molecule that induces adherens junction disruption, formerly called AF-2364, 1-(2,4-dichlorobenzyl)-IH-indazole-3-carbohydrazide], the event of AJ disruption was also associated with a transient iNOS (inducible nitric oxide synthase, NOS2) induction. Immunohistochemistry has illustrated that NOS2 was intensely accumulated in Sertoli and germ cells in the epithelium during adjudin-induced germ cell loss, with a concomitant accumulation of intracellular cGMP and an induction of PRKG but not cAMP or protein kinase A (cAMP-dependent protein kinase, PRKA). To identify the NOS-mediated downstream signaling partners, coimmunoprecipitation was used to demonstrate that NOS2 and eNOS (endothelial nitric oxide synthase, NOS3) were structurally associated with the N-cadherin (CDH2)/beta-catenin (CATNB)/actin complex but not the nectin-3 (poliovirus receptor-related 3, PVRL 3)/afadin (myeloid/lymphoid or mixed lineage-leukemia tranlocation to 4 homolog, MLLT4) nor the integrin beta1 (ITB1)-mediated protein complexes, illustrating the spatial vicinity of NOS with selected AJ-protein complexes. Interestingly, CDH2 and CATNB were shown to dissociate from NOS during the adjudin-mediated AJ disruption, implicating the CDH2/CATNB protein complex is the likely downstream target of the NO signaling. Furthermore, PRKG, the downstream signaling protein of NOS, was shown to interact with CATNB in the rat testis. Perhaps the most important of all, pretreatment of testes with KT5823, a specific PRKG inhibitor, can indeed delay the adjudin-induced germ cell loss, further validating NOS/NO regulates Sertoli-germ cell AJ dynamics via the cGMP/PRKG pathway. These results illustrate that the CDH2/CATNB-mediated adhesion function in the testis is regulated, at least in part, via the NOS/cGMP/PRKG/CATNB pathway.
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PMID:Regulation of Sertoli-germ cell adherens junction dynamics in the testis via the nitric oxide synthase (NOS)/cGMP/protein kinase G (PRKG)/beta-catenin (CATNB) signaling pathway: an in vitro and in vivo study. 1585 15


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