UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Towards dissecting the regulation of terminal differentiation, including growth arrest and apoptosis, myeloid differentiation primary response (MyD) genes, induced in the absence of de novo protein synthesis following induction of M1 myeloblastic leukemia cells for terminal differentiation have been isolated. MyD118 was one of the novel MyD genes cloned, subsequently observed also to be a primary response gene to TGF-beta, which induces M1 cells for growth arrest and apoptosis uncoupled from differentiation. The MyD118 encoded protein was observed to be remarkably similar to the protein encoded by Gadd45, a growth arrest and DNA damage induced gene, regulated in part by the tumor suppressor p53. Though evidence has accumulated that MyD118 functions as an important modulator of negative growth control both in hematopoietic and non-hematopoietic cells, its mechanism of action is unknown. To better understand the role(s) of MyD118 in negative growth control, we have analysed the expression and biological characteristics of the MyD118 protein, compared to the Gadd45 protein, in distinct pathways of growth arrest and apoptosis, including p53 dependent and independent pathways either coupled or uncoupled from differentiation. It is shown that MyD118 and Gadd45 differentially accumulated upon induction of distinct pathways of growth arrest and apoptosis; notably, MyD118, but not Gadd45, was induced by TGF-beta, whereas Gadd45, but not MyD118, was induced by activating wild type (wt) p53 function. It is also shown that MyD118 is a nuclear protein, which regardless of the pathway induced, predominantly localized within the cell nucleus, and interacted with the DNA replication and repair protein PCNA and the cyclin dependent kinase inhibitor P21WAF1/CIP1. MyD118 also modestly stimulated DNA repair in vitro. All of these characteristics were shared with Gadd45. Finally, it is demonstrated that MyD118, Gadd45 and p21 synergized in the suppression of colony formation by NIH3T3 cells. Taken together, these findings demonstrate that MyD118 and Gadd45 are representative of a new protein family that share remarkable functional similarities in the control of distinct pathways of negative growth, including the suppression of cellular growth and programmed cell death.
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PMID:The differentiation primary response gene MyD118, related to GADD45, encodes for a nuclear protein which interacts with PCNA and p21WAF1/CIP1. 870 May 17

The peri-ets (pets) site is a TG-rich element found immediately adjacent to two binding sites for the ets family member Elf-1 in the human immunodeficiency virus type 2 (HIV-2) enhancer. Enhancer activation in response to T cell stimulation by phorbol myristate acetate, phytohemagglutinin, soluble or cross-linked antibodies to the T cell receptor, or antigen is mediated through this site in conjunction with its two adjacent Elf-1 binding sites, PuB1 and PuB2, and a kappaB site. Site-specific mutation of the pets element significantly reduces inducible activation of this enhancer but does not affect its transactivation by HIV-2 tat or other viral transactivators. Similar TG-rich sequences adjacent to ets-binding sites have also been found to be functionally important in the human T-cell leukemia virus type I and murine Moloney leukemia virus enhancers. As the cellular factor binding to the pets site plays a significant role in regulating the HIV-2 enhancer in both T cells and monocytes, we have purified this protein from bovine spleens and demonstrate that it is 43 kDa in size. In addition, using glycerol gradient centrifugation, Southwestern blotting, electrophoretic mobility shift assays employing purified protein eluted from a gel, and a new in solution UV cross-linking competitive assay, we show that the dominant protein binding to the pets site is 43 kDa in size. These results indicate that a nuclear protein of 43 kDa binds specifically to the pets site of the HIV-2 enhancer and may mediate transcriptional activation of this important human pathogen in response to T cell stimulation. As retroviruses generally expropriate important human regulatory proteins for their own use, the 43-kDa pets factor is also likely to play a significant role in signal transduction in T cells and in other cellular processes.
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PMID:Purification of the pets factor. A nuclear protein that binds to the inducible TG-rich element of the human immunodeficiency virus type 2 enhancer. 870 55

Diseases resulting from infection by feline leukemia virus (FeLV) and several other retroviruses relate in part, to non-coding regulatory sequences within the viral long terminal repeat (LTR). Both enhancer repeats and mutations within the LTR have been implicated in FeLV related disease. In order to investigate the relationship between nucleotide sequence of the FeLV LTR and disease, tissues from 33 cats with different types of degenerative and proliferative FeLV-related disease were studied. An FeLV LTR region containing the putative transcriptional enhancer unit was amplified by polymerase chain reaction (PCR) from FeLV-infected tissues. Phylogenetic analysis of FeLV 3'unique (U3) sequences revealed only one meaningful grouping which contained 4 of the 5 antigen-negative lymphosarcomas (LSAs). No sequence duplications were found in any of the 33 FeLV U3 regions. Point mutations relative to the corresponding region of FeLV-A/Glasgow, were identified at 102 positions; 68 of these were accounted for by mutations at 5 locations. Only 1 point mutation was found within the leukemia virus b-simian virus 40-like core (LVb-CORE) site. However, the nuclear factor 1 (NF1) site contained 11 mutations, and the FeLV-specific (FLV-1) site contained 26 mutations. Most of the remaining mutations were upstream of the LVB site between glucocorticoid response element (GRE) and FLV-1. The 10 LSAs, particularly the 5 antigen-negative LSAs, deviated least from the corresponding sequence for FeLV-A/Glasgow. Conclusions were that the spectrum of neoplastic and non-neoplastic FeLV-related diseases investigated in this study, developed in the presence of FeLVs containing the single enhancer unit. The significance of the point mutations is unknown, however, those occurring with high frequency and within nuclear protein binding should be first to be investigated in functional studies.
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PMID:Sequence analysis of the putative viral enhancer in tissues from 33 cats with various feline leukemia virus-related diseases. 900 33

The percentage of non-cycling blast cells in children with untreated acute lymphoblastic leukaemia (ALL) was investigated by staining smears for statin, a nuclear protein specifically present in non-growing resting cells. Results were compared with purified normal CD34-positive progenitors. A low fraction of ALL and CD34-positive cells expressed statin (2.9 +/- 3.8% and 2.8 +/- 3.1%, respectively), the growth fraction assessed by staining for the nucleolar antigen p120 was 94% in both ALL and CD34-positive cell samples. From this analysis it can be concluded that the compartment of non-replicating cells in ALL as well as in normal CD34-positive precursor cells collected from peripheral blood is very small and that most cells are cycling.
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PMID:Acute lymphoblastic leukaemia in childhood: cell proliferation without rest. 902 26

The WT1 gene encodes a transcriptional regulator which during embryogenesis is involved in growth control and differentiation of diverse tissues. It is also expressed in few human malignancies, including acute leukemia. We tested 3 different monoclonal antibodies (MAbs H2, H7, HCl7) and the polyvalent serum WTC-19 for WT1 protein detection in mononuclear cell (MNC) preparations of 104 newly diagnosed acute leukemia patients. Using RT-PCR, these MNC preparations were also analyzed for WT1 gene expression. MAbs H2, H7 and HCl7 and the polyclonal WTC-19 exhibited nuclear immunoreactivity in 63 of 99, 28 of 56, 38 of 60 and 22 of 43 WT1 gene-expressing leukemia samples, respectively. With these antibodies, no WT1 immunoreactivity was found in MNCs from blood of healthy volunteers, from CD34+ progenitor cell-enriched leukapheresis products of patients conditioned for peripheral stem cell harvest or from reactive bone marrow. Contrary to WTC-19, all MAbs reacted highly specifically with the WT1 protein (0.71 vs. 1.0). The WT1 protein was heterogeneously detected in leukemia blast preparations by all antibodies, irrespective of cell morphology. Very few HL60 cells and blasts from newly diagnosed leukemia patients interspersed among normal blood MNCs (50 blasts among 5 x 10(5) MNCs) were easy to identify by indirect immunofluorescence using MAbs H2 and HCl7. Taken together, MAbs H2 and HCl7 were superior to MAb H7 and the polyvalent WTC-19 in detecting the WT1 nuclear protein.
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PMID:Detection by monoclonal antibodies of the Wilms' tumor (WT1) nuclear protein in patients with acute leukemia. 905 49

TLS (FUS) and the related gene EWS encode the N-terminal portion of many fusion oncoproteins involved in human sarcomas and leukemia. TLS is an RNA-binding nuclear protein that is identical to hnRNP P2 and may be implicated in mRNA metabolism. When RNA polymerase II is inhibited, TLS immunostaining in the nucleus is dramatically altered, from its normal diffuse nucleoplasmic pattern to accumulation in dense nuclease-resistant aggregates. Co-immunostaining with antibodies to fibrillarin or p80 coilin and immunoelectron microscopy revealed that the TLS aggregates are associated with the nucleolus and are distinct from other known structures such as the coiled body or the interchromatin granule. Injection of cells with an oligodeoxynucleotide that disrupts splicing does not result in redistribution of TLS, indicating that the event is specific to inhibition of transcription. Oncoproteins that contain the N-terminal domain from either TLS, EWS or their Drosophila homologue, SARFH (CAZ), are also targeted to the same structure. These findings suggest a correlation between the topogenic and transforming activities of TLS and EWS N-termini and imply the existence of cellular targets that are shared by the germ-line encoded proteins and their oncogenic derivatives.
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PMID:A topogenic role for the oncogenic N-terminus of TLS: nucleolar localization when transcription is inhibited. 905 42

The hematotoxicity of benzene, a human leukemogen, has been postulated to be mediated by reactive metabolites and involve cell damage caused by reactive oxygen species. Because expression of the transcription factors AP-1 and NF-kappaB is sensitive to the redox state in eukaryotic cells, the DNA binding activity of AP-1 and NF-kappaB was examined in HL-60 promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a microsomal hematotoxic metabolite of benzene. There was little AP-1 binding activity in nuclear extracts from control HL-60 cells based on electrophoretic mobility shift assays. Exposure to 0.1 microM MUC for 4 h resulted in significantly increased levels of nuclear protein with high sequence specificity for the consensus AP-1 sequence. In addition, electrophoretic mobility shift assays showed a strong increase in the binding of a factor to the NF-kappaB site. The latter was highest in nuclear extracts from HL-60 cells treated with 1.0 microM muconaldehyde and cultured for 4 h. Exposure of HL-60 cells to muconaldehyde resulted in an increase in c-fos and c-jun mRNA levels. Western blot analysis showed that the protein levels of c-jun increased in HL-60 cells treated with 1 microM muconaldehyde and cultured for 4-6 h and subsequently decreased gradually. Increased AP-1 binding was observed in bone marrow cells from B6C3F1 mice 2 h after administration of 440 mg/kg benzene. We suggest that increased gene expression of NF-kappaB and AP-1 binding activity and up-regulation of c-fos and c-jun may play a role in the mechanism of benzene leukemogenesis.
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PMID:Increased gene expression in human promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a hematotoxic benzene metabolite. 911 Dec 8

The myeloid cell nuclear differentiation antigen (MNDA) is a nuclear protein expressed specifically in developing cells of the human myelomonocytic lineage, including the end-stage monocytes/macrophages and granulocytes. Nuclear localization, lineage- and stage-specific expression, association with chromatin, and regulation by interferon alpha indicate that this protein is involved in regulating gene expression uniquely associated with the differentiation process and/or function of the monocyte/macrophage. MNDA does not bind specific DNA sequences, but rather a set of nuclear proteins that includes nucleolin (C23). Both in vitro binding assays and co-immunoprecipitation were used to demonstrate that MNDA also binds protein B23 (nucleophosmin/NPM). Three reciprocal chromosome translocations found in certain cases of leukemia/lymphoma involve fusions with the NPM/B23 gene, t(5;17) NPM-RARalpha, t(2;5) NPM-ALK, and the t(3;5) NPM-MLF1. In the current study, MNDA was not able to bind the NPM-ALK chimera originating from the t(2;5) and containing residues 1-117 of NPM. However, MNDA did bind the NPM-MLF1 product of the t(3;5) that contains the N-terminal 175 residues of NPM. The additional 58 amino acids (amino acids 117-175) of the NPM sequence that are contained in the product of the NPM-MLF1 fusion gene relative to the product of the NPM-ALK fusion appear responsible for MNDA binding. This additional NPM sequence contains a nuclear localization signal and clusters of acidic residues believed to bind nuclear localization signals of other proteins. Whereas NPM and nucleolin are primarily localized within the nucleolus, MNDA is distributed throughout the nucleus including the nucleolus, suggesting that additional interactions define overall MNDA localization.
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PMID:MNDA binds NPM/B23 and the NPM-MLF1 chimera generated by the t(3;5) associated with myelodysplastic syndrome and acute myeloid leukemia. 932 47

The RING3 gene encodes a 90-kDa mitogen-activated nuclear protein. In proliferating cells, including in leukemia, RING3 has serine-threonine kinase and autophosphorylation activities. The cloning of D26362, a gene closely related to RING3, suggests a gene family. RING3 and D26362 are also related to the Drosophila developmental gene fsh. A database search for further members of the RING3 family identified an EST derived from a testis-specific library. cDNA clones representing the full coding sequence of the gene were isolated. The gene encodes a protein of 947 amino acids with extensive homology to RING3, D26362, and fsh. Similar to these proteins, it possesses two bromodomain motifs and a PEST sequence. Northern analysis of 16 normal tissues and eight cancer cell lines shows transcripts of 3.5 and 4.0 kb expressed specifically in testis. The gene has been named BRDT (for bromodomain, testis specific). PCR analysis of a panel of monochromosomal human/rodent hybrid cell lines and the GeneBridge 4 panel of radiation hybrids localizes the gene to chromosome 1p between markers WI-7719 and WI-3099 (D1S2154).
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PMID:Identification and characterization of BRDT: A testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh. 936 77

The CREB-binding protein (CBP) is a large nuclear protein that regulates many signal transduction pathways and is involved in chromatin-mediated transcription. The translocation t(8;16)(p11;p13.3) consistently disrupts two genes: the CBP gene on chromosome band 16p13.3 and the MOZ gene on chromosome band 8p11. Although a fusion of these two genes as a result of the translocation is expected, attempts at detecting the fusion transcript by reverse transcriptase polymerase chain reaction (RT-PCR) have proven difficult; to date, only one in-frame CBP/MOZ fusion transcript has been reported. We therefore sought other reliable means of detecting CBP rearrangements. We applied fluorescence in situ hybridization (FISH) and Southern blot analyses to a series of AML patients with a t(8;16) and detected DNA rearrangements of both the CBP and the MOZ loci in all cases tested. All six cases examined for CBP rearrangements have breakpoints within a 13 kb breakpoint cluster region at the 5' end of the CBP gene. Additionally, we used a MOZ cDNA probe to construct a surrounding cosmid contig and detect DNA rearrangements in three t(8;16) cases, all of which display rearrangements within a 6 kb genomic fragment of the MOZ gene. We have thus developed a series of cosmid probes that consistently detect the disruption of the CBP gene in t(8;16) patients. These clones could potentially be used to screen other cancer-associated or congenital translocations involving chromosome band 16p13.3 as well.
Leukemia 1997 Dec
PMID:Detection of CBP rearrangements in acute myelogenous leukemia with t(8;16). 944 25

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