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)

Deletion of 11q23-q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, using both loss of heterozygosity analysis and customized microarray comparative genomic hybridization. LARG (leukemia-associated Rho guanine-nucleotide exchange factor) (also called ARHGEF12), identified from the analysed region, is frequently underexpressed in breast and colorectal carcinomas with a reduced expression observed in all breast cancer cell lines (n=11), in 12 of 38 (32%) primary breast cancers, 5 of 10 (50%) colorectal cell lines and in 20 of 37 (54%) primary colorectal cancers. Underexpression of the LARG transcript was significantly associated with genomic loss (P=0.00334). Hypermethylation of the LARG promoter was not detected in either breast or colorectal cancer, and treatment of four breast and four colorectal cancer cell lines with 5-aza-2'-deoxycytidine and/or trichostatin A did not result in a reactivation of LARG. Enforced expression of LARG in breast and colorectal cancer cells by stable transfection resulted in reduced cell proliferation and colony formation, as well as in a markedly slower cell migration rate in colorectal cancer cells, providing functional evidence for LARG as a candidate tumor suppressor gene.
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PMID:LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast and colorectal cancer. 1973 46

Although involved in processes leading to the emergence and development of hormone-dependent breast cancers, the estrogen receptor alpha (ERalpha) also prevents transformed cells from progressing toward a more aggressive phenotype. The transcriptional activity of ERalpha is mediated through two transactivation functions, called activation function 1 and 2, whose respective involvement varies in a cell-specific manner. Here, we identify the Rho/megakaryoblastic leukemia 1 (MKL1) signaling pathway as a main actor in controlling the cell-specific activity of both transactivation functions of ERalpha. Notably, we show that, when the coregulator MKL1 is sequestered in an inactive form by unpolymerized actin, the transcriptional activity of ERalpha mainly relies on the activation function 1. The activation of MKL1, which results from its dissociation from unpolymerized actin, promoted by the ability of Rho to support polymeric actin accumulation, silences the activation function 1 of ERalpha and allows the receptor to mainly act through its activation function 2. Importantly, this switch in the respective contribution exerted by both transactivation functions is correlated with an impaired ability of ERalpha to efficiently transactivate estrogen-regulated reporter genes. MKL1 is further shown to be present on estrogen-responsive genes in vivo. Interestingly, the Rho/MKL1 signaling pathway is activated during the epithelial-mesenchymal transition. A reduced transactivation efficiency of ERalpha, resulting from the activation of this pathway, may therefore suppress the protective role exerted by ERalpha toward tumor progression and invasiveness.
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PMID:Repression of the estrogen receptor-alpha transcriptional activity by the Rho/megakaryoblastic leukemia 1 signaling pathway. 1982 2

The C3 transferases from Clostridium botulinum (C3bot) and Clostridium limosum (C3lim) mono-ADP-ribosylate and thereby inactivate RhoA, -B and -C of eukaryotic cells. Due to their extremely poor cellular uptake, C3 transferases were supposed to be exoenzymes rather than exotoxins, challenging their role in pathogenesis. Here, we report for the first time that low concentrations of both C3lim and C3bot are selectively internalized into macrophages/monocytes in less than 3 h, inducing the reorganization of the actin cytoskeleton by ADP-ribosylation of Rho. We demonstrate that C3 transferases are internalized into the cytosol of macrophages/monocytes via acidified early endosomes. Bafilomycin A1, an inhibitor of endosomal acidification, protected J774A.1 macrophages and human promyelotic leukaemia cells (HL-60) from intoxication by C3. Moreover, confocal laser scanning microscopy revealed colocalization of C3 with early endosomes. An extracellular acidic pulse enabled direct translocation of cell surface-bound C3 across the cytoplasmic membrane to the cytosol. In line with this finding, both C3 proteins exhibited membrane activity in lipid bilayer membranes only under acidic conditions (pH < 5.5). In conclusion, we identified macrophages/monocytes as target cells for clostridial C3 transferases and shed light on their selective uptake mechanism, which might contribute to understand the role of C3 transferases in pathogenesis.
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PMID:Selective and specific internalization of clostridial C3 ADP-ribosyltransferases into macrophages and monocytes. 1984 27

RhoH is a hematopoietic-specific, GTPase-deficient member of the Rho GTPase family that functions as a regulator of thymocyte development and T-cell receptor signaling by facilitating localization of zeta-chain-associated protein kinase 70 (ZAP70) to the immunological synapse. Here we investigated the function of RhoH in the B-cell lineage. B-cell receptor (BCR) signaling was intact in Rhoh(-/-) mice. Because RhoH interacts with ZAP70, which is a prognostic factor in B-cell chronic lymphocytic leukemia (CLL), we analyzed the mRNA levels of RhoH in primary human CLL cells and showed a 2.3-fold higher RhoH expression compared with normal B cells. RhoH expression in CLL positively correlated with the protein levels of ZAP70. Deletion of Rhoh in a murine model of CLL (Emu-TCL1(Tg) mice) significantly delayed the accumulation of CD5(+)IgM(+) leukemic cells in peripheral blood and the leukemic burden in the peritoneal cavity, bone marrow and spleen of Rhoh(-/-) mice compared with their Rhoh(+/+) counterparts. Phosphorylation of AKT and ERK in response to BCR stimulation was notably decreased in Emu-TCL1(Tg);Rhoh(-/-) splenocytes. These data suggest that RhoH has a function in the progression of CLL in a murine model and show RhoH expression is altered in human primary CLL samples.
Leukemia 2010 Jan
PMID:Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia. 1984 97

The Bcr-Abl protein is a marker for malignant transformation in chronic myeloid leukemia and in acute lymphoblastic leukemia. There are three Bcr-Abl chimeras known so far, p190, p210 and p230. The only structural difference between the three Bcr-Abl proteins is the presence of DH and PH domains from the Bcr gene in p210 and p230. The Bcr-Abl DH domain is functioning as a guanine nucleotide exchange factor for Rho family of small GTPases. The PH domain confers binding to phosphoinositides but some PH domains have also been found to bind specific target proteins. Here we show that the PH domain from Bcr-Abl binds a number of proteins involved in vital cellular processes. These proteins include PLCvarepsilon, Zizimin1, tubulin and SMC1. The revelation of the role of the Bcr-Abl PH domain in leukemogenesis is likely to provide clues to the molecular mechanisms underlying the phenotypes of Bcr-Abl positive leukemia and could therefore provide tools for the identification of targets for the development of therapeutic treatments.
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PMID:Novel role of pleckstrin homology domain of the Bcr-Abl protein: analysis of protein-protein and protein-lipid interactions. 1994 85

Rho family GTPases are intracellular signaling proteins regulating multiple pathways involved in cell actomyosin organization, adhesion, and proliferation. Our knowledge of their cellular functions comes mostly from previous biochemical studies that used mutant overexpression approaches in various clonal cell lines. Recent progress in understanding Rho GTPase functions in blood cell development and regulation by gene targeting of individual Rho GTPases in mice has allowed a genetic understanding of their physiologic roles in hematopoietic progenitors and mature lineages. In particular, mouse gene-targeting studies have provided convincing evidence that individual members of the Rho GTPase family are essential regulators of cell type-specific functions and stimuli-specific pathways in regulating hematopoietic stem cell interaction with bone marrow niche, erythropoiesis, and red blood cell actin dynamics, phagocyte migration and killing, and T- and B-cell maturation. In addition, deregulation of Rho GTPase family members has been associated with multiple human hematologic diseases such as neutrophil dysfunction, leukemia, and Fanconi anemia, raising the possibility that Rho GTPases and downstream signaling pathways are of therapeutic value. In this review we discuss recent genetic studies of Rho GTPases in hematopoiesis and several blood lineages and the implications of Rho GTPase signaling in hematologic malignancies, immune pathology. and anemia.
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PMID:Rho GTPases in hematopoiesis and hemopathies. 1996 43

We tested the hypothesis that the basal release of nitric oxide (NO) from endothelial cells modulates contractile activity in the corpus cavernosum (CC) via inhibition of the RhoA/Rho-kinase signaling pathway. Cavernosal strips from wild-type (WT), endothelial nitric-oxide synthase knockout [eNOS(-/-)], and neuronal nitric-oxide synthase knockout [nNOS(-/-)] mice were mounted in myographs, and isometric force was recorded. mRNA and protein expression of key molecules in the RhoA/Rho-kinase pathway were analyzed by real-time polymerase chain reaction and Western blot, respectively. The cGMP levels were determined. The Rho-kinase inhibitors (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632) and (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl] homopiperazine (H-1152) reduced cavernosal contractions evoked by phenylephrine or electrical field stimulation (EFS) in a concentration-dependent manner, although this inhibition was less effective in tissues from eNOS(-/-) mice. Y-27632 enhanced relaxations induced by sodium nitroprusside, EFS, and NO (administered as acidified NaNO2) without affecting the cGMP content of the cavernosal strips. This enhancement was less prominent in CC from eNOS(-/-). The protein expression of RhoA, Rho-guanine dissociation inhibitor, and Rho-kinase beta did not differ among the strains. However, in eNOS(-/-) CC, the protein expression of Rho-kinase alpha and both mRNA and protein expression of p115-Rho-associated guanine exchange factor (RhoGEF), PDZ-RhoGEF, and leukemia-associated RhoGEF were up-regulated. Phosphorylation of MYPT1 at Thr696 was higher in tissues from eNOS(-/-) mice. A high concentration of Y-27632 significantly enhanced NO release in CC stimulated by EFS. These results suggest a basal release of NO from endothelial cells, which inhibits contractions mediated by the RhoA/Rho-kinase pathway and modulates the expression of proteins related to this pathway in mouse CC. It indicates that endothelial integrity is essential to the maintenance of erectile function.
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PMID:Up-regulation of the RhoA/Rho-kinase signaling pathway in corpus cavernosum from endothelial nitric-oxide synthase (NOS), but not neuronal NOS, null mice. 2009 96

To activate the GTPase Rac in rat basophilic leukemia (RBL) cells and mouse bone marrow-derived mast cells (BMMC) a TAT fusion toxin of Bordetella dermonecrotic toxin (DNT-TAT) was constructed. The fusion toxin activated Rac1 and RhoA in vitro but only Rac in RBL cells and BMMC. DNT-TAT caused an increase in inositol phosphate formation, calcium mobilization, ERK activation and degranulation of mast cells. All these effects were inhibited by the Rho GTPase-inactivating Clostridium difficile toxin B and Clostridium sordellii lethal toxin. Also the calcium ionophore A23187 caused mast cell activation, including ERK phosphorylation, by processes involving an activation of Rac. The data indicate pleiotropic functions of Rac in mast cell activation.
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PMID:Pleiotropic role of Rac in mast cell activation revealed by a cell permeable Bordetella dermonecrotic fusion toxin. 2021 24

Mitochondrial bioenergetics and reactive oxygen species (ROS) often play important roles in cellular stress mechanisms. In this study we investigated how these factors are involved in the stress response triggered by resazurin (Alamar Blue) in cultured cancer cells. Resazurin is a redox reactive compound widely used as reporter agent in assays of cell biology (e.g. cell viability and metabolic activity) due to its colorimetric and fluorimetric properties. In order to investigate resazurin-induced stress mechanisms we employed cells affording different metabolic and regulatory phenotypes. In HL-60 and Jurkat leukemia cells resazurin caused mitochondrial disintegration, respiratory dysfunction, reduced proliferation, and cell death. These effects were preceded by a burst of ROS, especially in HL-60 cells which were also more sensitive and contained autophagic vesicles. Studies in Rho(0) cells (devoid of mitochondrial DNA) indicated that the stress response does not depend on the rates of mitochondrial respiration. The anti-proliferative effect of resazurin was confirmed in native acute myelogenous leukemia (AML) blasts. In conclusion, the data suggest that resazurin triggers cellular ROS production and thereby initiates a stress response leading to mitochondrial dysfunction, reduced proliferation, autophagy, and cell degradation. The ability of cells to tolerate this type of stress may be important in toxicity and chemoresistance.
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PMID:Cellular stress induced by resazurin leads to autophagy and cell death via production of reactive oxygen species and mitochondrial impairment. 2056 17

This study tested the hypothesis that TRAIL could play a role in regulating monocyte migration. TRAIL has been widely studied for its anti-tumor function and signaling mechanisms. Using chemotaxis and mouse air-pouch model analyses, we determined that TRAIL-induced chemotactic migration of THP-1 human leukemia and LPS-primed primary human monocytes as well as LPS-stimulated BALB/c mouse monocytes in vivo. To expand the understanding of the TRAIL signaling pathway in this process, we found that the TRAIL receptor DR4 was highly expressed in THP-1 and LPS-primed primary monocytes but not in the non-primed primary monocytes. DR4 neutralization antibody specifically suppressed TRAIL-induced migration of the monocytes. Furthermore, PI3K, Rho GTPase and its downstream effectors, MLC and Pak1, were activated during cell migration. PI3K inhibitors and dominant negative mutants of RhoGTPase blocked monocyte migration toward TRAIL, indicating that PI3K and RhoGTPases were involved in the migration signaling. The DR4 neutralization antibody blocked the activation of PI3K and Rho GTPase effectors in the cells. Thus, these data support the hypothesis that TRAIL induces monocyte migration mediated by TRAIL receptor DR4 via the RhoGTPase signaling pathway. This study is expected to provide novel evidence of the non-apoptotic function of TRAIL in immune defense.
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PMID:Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces chemotactic migration of monocytes via a death receptor 4-mediated RhoGTPase pathway. 2063 29


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