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)

Three of the ets oncogene superfamily members v-ets, Spi-1/PU.1 and Fli-1, have been shown to be directly involved in retroviral-mediated acute erythroleukemias. The Fli-1 gene was found to be rearranged in 75% of the erythroleukemias induced by Friend murine leukemia virus (F-MuLV), suggesting that it could play a key role in cellular transformation. We have previously isolated and characterized the human Fli-1 gene and have found it to be highly homologous (80%) to the human erg-2 gene. Human Fli-1 was also shown to be rearranged in Ewing's sarcoma cases, in which the amino-terminal region of the Fli-1 gene was replaced with a novel coding region of a putative RNA-binding protein, EWS. In this report, we show that the recombinant Fli-1 protein expressed in bacteria binds to DNA in a sequence-specific manner. It appears that Fli-1 and erg proteins fall into the category of ets proteins that recognize limited ets target sequences, unlike c-ets-1, ets-2 and Elk-1. The Fli-1 gene was found to activate the transcription of the reporter gene that was linked to Fli-1 target sequences, suggesting that Fli-1 is a sequence-specific transcriptional activator. Deletion analysis revealed the presence of two autonomous transcriptional activation domains, one at the amino-terminal region (amino-terminal transcriptional activation domain, ATA) and the other at the carboxy-terminal region (carboxy-terminal transcriptional activation domain, CTA). Secondary structural analysis of ATA and CTA domains revealed the presence of helix-loop-helix (H-L-H) and/or turn-loop-turn (T-L-T) regions. From these results it appears that a portion of the Fli-1 ATA domain (H-L-H region) was replaced by the amino-terminal domain of EWS gene in Ewing's sarcoma cases. Therefore alteration in the transcriptional activation function of Fli-1 may be responsible for human malignancies such as sarcomas, leukemias and lymphomas in which this gene is rearranged.
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PMID:Analysis of the DNA-binding and transcriptional activation functions of human Fli-1 protein. 833 42

Leukemia, a form of haematological malignancy, is a multi-stage disease and a wide range of diverse genes has been speculated to correlate with its initiation and development. Ras has been speculated to be an initiating gene for haematological malignancy, but more investigation will be needed to determine the genes associated with the progression of the disease. 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat leukemia provides a good tool for research into various stages of the disease. The entire coding regions of p53 and ras genes were examined for mutations in the present study. In this experiment, we used fluorescence-labeled polymerase chain reaction single-stranded conformation polymorphism analysis (PCR-SSCP) and direct sequencing to detect mutations of both genes on rat erythroleukemia. Fifteen out of 18 (83.3%) rat leukemias were found to have N-ras codon 61 mutation, consistent with previous results. The result of direct sequencing showed a single base substitution (CAA to CTA), resulting in an amino-acid change from Gln to Leu. No mutations were found in H-ras, K-ras or codon 12 of N-ras. The incidence of p53 gene mutation was 16.6% (3/18) in rat leukemia at late-stage. In the present study, mutation of the p53 gene was detected in three DMBA-induced leukemias as follows: a single-base substitution (CAT to CGT) at codon 177 (exon 5), resulting in an amino-acid change from Arg to Leu, a CGG to CTG/CGG changed at codon 211 (exon 6) resulting in an amino-acid change from His to Arg/His, and a GGG to TGG at codon 242 (exon 6) resulting in an amino-acid change from Gly to Trp, respectively. Thus, mutations of p53 gene do not seem to respond to the carcinogenesis of the DMBA-induced leukemia, in contrast to mutation of the N-ras oncogene, and may possibly be involved in the progress of multi-stage leukemogenesis.
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PMID:Incidence of p53 and ras gene mutations in DMBA-induced rat leukemias. 1238 83

Targeting the mitotic machinery using anti-mitotic drugs for elimination of cancer cells is a century-old concept, which continues to be routinely used as a first line of treatment in the clinic. However, patient response remains unpredictable and drug resistance limits effectiveness of these drugs. Cancer cells exit from drug-induced mitotic arrest (mitotic slippage) to avoid subsequent cell death which is thought to be a major mechanism contributing to this resistance. The tumor cells that acquire resistance to anti-mitotic drugs have chromosomal instability (CIN) and are often aneuploid. In this review, we outline the key mechanisms involved in dictating the cell fate during perturbed mitosis and how these processes impede the efficacy of anti-mitotic therapies. Further, we emphasize the recent work from our laboratory, which highlights the functional role of CEP55 in protecting aneuploid cells from death. We also discuss the rationale of targeting CEP55 in vivo, which could prove to be a novel and effective therapeutic strategy for sensitizing cells to microtubule inhibitors and might offer significantly improved patient outcome. Abbreviations: APC/C: Anaphase-Promoting Complex/Cyclosome; BAD: BCL2-Associated agonist of cell Death; BAK1: BCL2 Antagonist Kinase1; BAX: BCL2-Associated X; BCL2: B-cell Chronic Lymphocytic Leukaemia (CLL)/Lymphoma 2; BH: BCL2 Homology Domain; BID: BH3-Interacting domain Death agonist; BIM: BCL2-Interacting Mediator of cell death; BUB: Budding Uninhibited by Benzimidazoles; CDC: Cell Division Cycle; CDH1: Cadherin-1; CDK1: Cyclin-Dependent Kinase 1; CEP55: Centrosomal Protein (55 KDa): CIN: Chromosomal Instability; CTA: Cancer Testis Antigen; EGR1: Early Growth Response protein 1; ERK: Extracellular Signal-Regulated Kinase; ESCRT: Endosomal Sorting Complexes Required for Transport; GIN: Genomic Instability; MAD2: Mitotic Arrest Deficient 2; MCL1: Myeloid Cell Leukemia sequence 1; MPS1: Monopolar Spindle 1 Kinase; MYT1: MYelin Transcription factor 1; PLK1: Polo Like Kinase 1; PUMA: p53-Upregulated Mediator of Apoptosis; SAC: Spindle Assembly Checkpoint; TAA: Tumor-Associated Antigen.
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PMID:Mitotic slippage: an old tale with a new twist. 3060 Oct 84