Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 p53 gene encodes a nuclear phosphoprotein and is now considered as a tumor suppressor gene. Mutations of the p53 gene have frequently been observed in several types of solid tumors and are believed to be implicated in the development of these tumors. Recent studies have shown that the p53 gene is altered in chronic myelogenous leukemia (CML) in blast crisis. In CML, alterations of the p53 gene may play an important role in the development of blast crisis. More recently, p53 mutations have been reported in other types of hematologic neoplasms, such as acute leukemia, adult T-cell leukemia, and malignant lymphoma. These observations suggest that inactivation of the p53 gene is involved in the tumorigenesis of various types of hematologic neoplasms.
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PMID:[Mutations of the p53 gene in hematologic neoplasms]. 151 57

Bovine leukemia virus (BLV) and the human T-cell leukemia virus types I and II comprise a unique retrovirus subfamily which has evolved complex strategies for the regulation of gene expression. A transcriptional control circuit has been characterized in both human and bovine systems in which cis-acting promoter control elements are responsive to trans-acting factors encoded in the pX region of the virus. The BLV pX mRNA encoding the transcriptional trans-acting factor is translated in an alternate reading frame to produce an 18-kilodalton nuclear phosphoprotein, p18. A function for this protein was revealed in cotransfection experiments using mutated BLV proviruses in combination with pX expression plasmids. These experiments indicated that p18 was required for the accumulation of viral mRNAs representing full-length (genomic) and single-spliced (env) transcripts. In contrast, synthesis of the double-spliced pX mRNA was not influenced by p18 expression. Large regional deletions and substitutions of provirus sequences localized elements essential for p18 regulation to the 3' long terminal repeat. Furthermore, sequences within a 250-nucleotide region between the AATAAA signal and poly(A) site were found to be essential for efficient virus mRNA 3'-end processing and response to p18 regulation.
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PMID:trans-acting regulation of bovine leukemia virus mRNA processing. 283 74

Bovine leukemia virus, like its closest relatives the human T-cell leukemia virus types I and II, contains a 1.8-kilobase X region between the env gene and the 3' long terminal repeat. In this communication, we report the detection and characterization of a subgenomic mRNA from which this X region is presumably translated. This mRNA was produced by a complex splicing mechanism which resulted in juxtaposition of the 5' end of the env gene and the two overlapping X-region open reading frames. Translation of this mRNA could yield at least two distinct proteins depending on which initiation codon is used. Detection of the protein encoded by the BLV X-region long open reading frame has been reported (N. Sagata, J. Tsuzuku-Kawamura, M. Nagayoshi-Aida, F. Shimizu, K.-I. Imagawa, and Y. Ikawa, Proc. Natl. Acad. Sci. USA 82:7879-7883, 1985). Using synthetic peptide antisera, we detected a protein encoded by the short open reading frame in virus-infected cells. The protein migrated in sodium dodecyl sulfate-polyacrylamide gels with an apparent molecular weight of 19,000. It is a nuclear phosphoprotein.
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PMID:Expression of the bovine leukemia virus X region in virus-infected cells. 303 84

Expression of the gene encoding the nuclear phosphoprotein p53 (a proto-oncogene classified in the same functional family as c-myc and E1a adenovirus gene) was examined in a human T-cell leukemia (KE-37R cell line). No p53 (or a modified product) could be detected by immunoprecipitation with monoclonal antibodies P Ab 421 and P Ab 122 in KE-37R cell extracts, and no p53-specific RNA was characterized by Northern blot analysis. Southern blot using a murine p53 cDNA clone as a probe, did not reveal any gross rearrangement in the structure of the gene. However, this molecular probe was not suited for investigating the 5' end of the gene which contains the promoter and the non coding exon 1. It is interesting to notice that in KE-37R cells, c-myc has been activated by a t(8; 14) (q24; q11) translocation, suggesting that the c-myc product might substitute to some functions normally requiring p53.
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PMID:[Lack of expression of the protein p53 gene in a human T-cell leukemia line]. 312 85

The product of the human retinoblastoma gene (pRb) is a nuclear phosphoprotein that is thought to function as a tumor suppressor. Heterogeneous expression of the Rb gene product contributes to the genesis of a diverse group of human neoplasma such as breast, prostate, small cell lung, bladder carcinomas and leukemia. The clinical importance of Rb function demands a reproducible Rb immunohistochemical assay to distinguish Rb+ from Rb- tumor cells. We report an immunohistochemical study to detect Rb protein in a series of 50 invasive breast cancers. Our results support the hypothesis that the Rb gene functions as both a cell growth factor and a tumor suppressor.
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PMID:Expression of retinoblastoma protein in human breast cancer: an immunohistochemical study. 793 56

The role of the nuclear phosphoprotein c-Myc has been examined with respect to the regulation of 1-beta-D-arabinofuranosylcytosine (ara-C)-induced apoptosis in human leukemia cells exposed to bryostatin 1 and other pharmacologic protein kinase C (PKC) activators. Pretreatment of HL-60 cells for 24 hr with 10 nM bryostatin 1 significantly potentiated the ability of ara-C (10 microM; 6 hr) to induce apoptosis without reducing the expression of c-Myc protein. In contrast, equivalent exposure to the stage 2 tumor-promoting PKC activator mezerein (10 nM) in conjunction with ara-C reduced c-Myc levels by 87% and failed to potentiate apoptosis. Co-administration of bryostatin 1 with mezerein before ara-C prevented down-regulation of c-Myc and augmented cell death, whereas co-treatment with the calcium ionophore A23187 (250 nM) and bryostatin 1 reduced c-Myc levels by 80% and abrogated the increase in ara-C-induced apoptosis. When cells were exposed for 24 hr to a c-myc antisense oligonucleotide (AS-ODN;10 microM) but not to a scrambled sequence ODN (SS-ODN) prior to ara-C, c-Myc expression was reduced by 81%, and apoptosis and cell viability were unperturbed. However, AS-ODN (but not SS-ODN) reduced c-Myc protein in cells pre-exposed to bryostatin 1 by 74% and abrogated potentiation of ara-C-induced apoptosis. The actions of c-myc AS-ODN did not stem from proximal G1 arrest/differentiation or biochemical events, since they were not associated with a reduction in the S-phase cell fraction, p21(WAF1/CIP1) induction, pRb hypophosphorylation, or alterations in ara-C metabolism. Together, these findings indicate that HL-60 cell apoptosis proceeds by both c-Myc-dependent and -independent pathways, and that only the former are involved in the potentiation of ara-C-mediated cell death by bryostatin 1.
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PMID:Potentiation of ara-C-induced apoptosis by the protein kinase C activator bryostatin 1 in human leukemia cells (HL-60) involves a process dependent upon c-Myc. 933 72

The Rex trans-regulatory protein of human T-cell leukemia virus type 1 (HTLV-1) is required for the nuclear export of incompletely spliced and unspliced viral mRNAs and is therefore essential for virus replication. Rex is a nuclear phosphoprotein that directly binds to its cis-acting Rex response element RNA target sequence and constantly shuttles between the nucleus and cytoplasm. Moreover, Rex induces nuclear accumulation of unspliced viral RNA. Three protein domains which mediate nuclear import-RNA binding, nuclear export, and Rex oligomerization have been mapped within the 189-amino-acid Rex polypeptide. Here we identified a different region in the carboxy-terminal half of Rex which is also required for biological activity. In inactive mutants with mutations that map within this region, as well as in mutants that are deficient in Rex-specific multimerization, Rex trans activation could be reconstituted by fusion to a heterologous leucine zipper dimerization interface. The intracellular trafficking capabilities of wild-type and mutant Rex proteins reveal that biologically inactive and multimerization-deficient Rex mutants are still efficiently translocated from the nucleus to the cytoplasm. This observation indicates that multimerization is essential for Rex function but is not required for nuclear export. Finally, we are able to provide an improved model of the HTLV-1 Rex domain structure.
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PMID:Multimer formation is not essential for nuclear export of human T-cell leukemia virus type 1 Rex trans-activator protein. 976 6

PML is a nuclear phosphoprotein that was first identified as part of a translocated chromosomal fusion product associated with acute promyelocytic leukaemia (APL). PML localises to distinct nuclear multi-protein complexes termed ND10, Kr bodies, PML nuclear bodies and PML oncogenic domains (PODs), which are disrupted in APL and are the targets for immediate early viral proteins, although little is known about their function. In a yeast two-hybrid screen, we first identified a ubiquitin-like protein named PIC1 (now known as SUMO-1), which interacts and co-localises with PML in vivo. More recent studies have now shown that SUMO-1 covalently modifies a number of target proteins including PML, RanGAP1 and IkappaBalpha and is proposed to play a role in either targeting modified proteins and/or inhibiting their degradation. The precise molecular role for the SUMO-1 modification of PML is unclear, and the specific lysine residues within PML that are targeted for modification and the PML sub-domains necessary for mediating the modification in vivo are unknown. Here we show that SUMO-1 covalently modifies PML both in vivo and in vitro and that the modification is mediated either directly or indirectly by the interaction of UBC9 with PML through the RING finger domain. Using site-specific mutagenesis, we have identified the primary PML-SUMO-1 modification site as being part of the nuclear localisation signal (Lys487 or Lys490). However SUMO-1 modification is not essential for PML nuclear localisation as only nuclear PML is modified. The sequence of the modification site fits into a consensus sequence for SUMO-1 modification and we have identified several other nuclear proteins which could also be targets for SUMO-1. We show that SUMO-1 modification appears to be dependant on the correct subcellular compartmentalisation of target proteins. We also find that the APL-associated fusion protein PML-RARA is efficiently modified in vitro, resulting in a specific and SUMO-1-dependent degradation of PML-RARA. Our results provide significant insights into the role of SUMO-1 modification of PML in both normal cells and the APL disease state.
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PMID:SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation. 988 91

The E-26 transforming specific (ETS)-related gene, TEL, also known as ETV6, encodes a strong transcription repressor that is rearranged in several recurring chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. TEL is a nuclear phosphoprotein that is widely expressed in all normal tissues. TEL contains a DNA-binding domain at the C terminus and a helix-loop-helix domain (also called a pointed domain) at the N terminus. The pointed domain is necessary for homotypic dimerization and for interaction with the ubiquitin-conjugating enzyme UBC9. Here we show that the interaction with UBC9 leads to modification of TEL by conjugating it to SUMO-1. The SUMO-1-modified TEL localizes to cell-cycle-specific nuclear speckles that we named TEL bodies. We also show that the leukemia-associated fusion protein TEL/AML1 is modified by SUMO-1 and found in the TEL bodies, in a pattern quite different from what we observe and report for AML1. Therefore, SUMO-1 modification of TEL could be a critical signal necessary for normal functioning of the protein. In addition, the modification by SUMO-1 of TEL/AML1 could lead to abnormal localization of the fusion protein, which could have consequences that include contribution to neoplastic transformation.
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PMID:Posttranslational modification of TEL and TEL/AML1 by SUMO-1 and cell-cycle-dependent assembly into nuclear bodies. 1107 23

The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein is a 40-kDa nuclear phosphoprotein which functions in the viral replication cycle as a transcriptional trans-activator of the viral long terminal repeat. Tax interacts with a variety of different transcription factors, including the CREB binding protein (CBP)/p300 family of transcriptional accessory proteins. We demonstrate that a Tax mutant defective for the CBP/p300 interaction retains the capacity to immortalize primary human T lymphocytes when it is expressed from a functional molecular clone of HTLV-1. Thus, immortalization of HTLV-1-infected cells appears to be independent of Tax-induced alterations in CBP/p300 function.
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PMID:Immortalization of T lymphocytes by human T-cell leukemia virus type 1 is independent of the tax-CBP/p300 interaction. 1109 Feb 2


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