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)

In retroviruses, the viral protease (PR) is released as a mature protein by cleavage of Gag, Gag-Pro, or Gag-Pro-Pol precursor polypeptides. In avian sarcoma and leukemia viruses (ASLV), PR forms the C-terminal domain of Gag. Based on the properties of a mutation (cs22) in the cleavage site between the upstream NC domain and the PR domain, the proteolytic liberation of PR previously was inferred to be essential for processing of Gag and Pol proteins. To study this process in more detail, we have analyzed the effects that several mutations at the NC-PR cleavage site have on proteolytic processing in virus-like particles expressed in COS and quail cells. Mutant Gag proteins carrying the same mutations also were synthesized in vitro and tested for processing with purified PR. In both types of studies, N-terminal sequencing of the liberated PR domain was carried out to exactly identify the site of cleavage. Finally, synthetic peptides corresponding to the mutant proteins were assessed for the ability to act as substrates for PR. The results were all consistent and led to the following conclusions. (i) In vivo, if normal processing between NC and PR is prevented by mutations, limited cleavage occurs at a previously unrecognized alternative site three amino acids downstream, i.e., in PR. This N-terminally truncated PR is inactive as an enzyme, as inferred from the global processing defect in cs22 and a similar mutant. (ii) In Gag proteins translated in vitro, purified PR cleaves this alternative site as rapidly as it does the wild-type site. (iii) Contrary to previously accepted rules describing retroviral cleavage sites, an isoleucine residue placed at the P1 position of the NC-PR cleavage site does not hinder normal processing. (iv) A proline residue placed at the P2 position in this cleavage site blocks normal processing.
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PMID:Analysis of cleavage site mutations between the NC and PR Gag domains of Rous sarcoma virus. 898 69

Leukemia in the soft-shell clam, Mya arenaria, is characterized by tumor cells which are detected initially in the hemolymph. This disease is much more common in clams inhabiting polluted waters, suggesting an environmental component to its pathogenesis. In this study, leukemia cells were identified using a murine monoclonal antibody, 1E10, which recognizes a leukemia-specific protein expressed by tumor cells. Mutant p53 protein was detected using a murine monoclonal antibody (PAb 240) which reacts with mutant p53. Using immunofluorescence, the reactivity of clam cells to the 1E10 antibody was evaluated along with mutant p53 protein reactivity. Reverse transcriptase-polymerase chain reactions followed by sequence analyses were utilized to examine clams with hemocytes reacting with the p53 antibody for possible p53 gene mutations. Mutant p53 protein was expressed by tumor cells from five animals with advanced disease (in which greater than 90% of cells reacted with 1E10). A C-->G transversion was detected at the end of exon 6 from two of the five animals that reacted with both the mutant p53 antibody and 1E10. This substitution changes the amino acid of this codon from proline to alanine. Overall, our results suggest that environmentally induced alterations in p53 can contribute to the pathogenesis of leukemia in soft-shell clams inhabiting polluted water and/or sediment.
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PMID:Detection of mutant p53 in clam leukemia cells. 916 98

In the 239-261 region of the surface glycoprotein of HTLV-I, we delineated five epitopes recognized by antibodies present in sera from HTLV-I infected patients. Three epitopes are located between the amino acids 252 and 261, one is of a linear type and the two others of a conformational type. One epitope is comprised between amino acids 244 and 249. The last epitope described lies between the amino acids 244 and 257 and strictly requires the presence of a serine at position 250 for its recognition. When patients are infected by viral isolates presenting a substitution of the serine at position 250 by a proline, no antibodies recognizing the 244-257 region could be found. Altogether, our data demonstrate that the immunodominant 239-261 region is complex and is subject to antigenic variability.
Leukemia 1997 Apr
PMID:Antigenic variability of an immunodominant region (239-261) of the surface glycoprotein of HTLV-I. 920 83

The majority of neutralizing antibodies of HTLV-I are directed against linear epitopes of the envelope surface glycoprotein (gp46) in the immunodominant region 175-199. Although gp46 presents a remarkable degree of conservation, the substitution of the proline at position 192 by a serine is described for 10 isolates among the 54 sequenced ones. This amino acid substitution is known to induce an important change in the orientation of the exposed residues of this region and has drastic consequences on the immunogenicity of the neutralizable epitopes located in this region. We developed monoclonal antibodies directed against epitopes located in this region containing a proline or a serine at position 192. The six monoclonal antibodies obtained recognize the gp46 at the surface of living HTLV-I producing cells, two of them are specific of a 190-197 epitope with a serine at position 192. This demonstrates that the antigenicity of this epitope differs depending on the presence of a proline or a serine at position 192. Altogether, these results demonstrate that the immunodominant neutralizable region 175-199 is antigenically variable.
Leukemia 1997 Apr
PMID:Antibodies directed against a variable and neutralizable region of the HTLV-I envelope surface glycoprotein. 920 90

The AML1 is the most commonly involved transcription factor gene in human leukemias and forms chimeric transcription factor genes, namely, AML1/MTG8 by the t(8;21), AML1/EVI-1 by the t(3;21), and TEL/AML1 by the t(12;21). The AML1a and AML1b, two isoforms of the AML1 protein, are translated from the AML1 gene by the alternative splicing. The shorter form and longer form are named as AML1a and AML1b, respectively. The AML1b contains the runt homology domain as a DNA-binding domain and the serine/proline/threonine-rich domain (PST domain) as a putative transactivation domain. The AML1a contains only the runt homology domain, but not the PST domain. The AML1b has a transactivation ability through the PEBP2 site and stimulates differentiation of myeloid cells. On the other hand, AML1a cna bind the PEBP2 site, but does not show a transactivation ability through the PEBP2 site. The AML1a dominantly suppresses transactivation induced by the AML1b and has the ability to block differentiation of myeloid cells. It is a reasonable hypothesis that the molecular ratio of AML1a to AML1b in myeloid cells could determine whether they proliferate or undergo a terminal differentiation.
Leukemia 1997 Apr
PMID:Leukemogenesis by the chromosomal translocations. 920 70

Several tyrosine kinases such as Jak1, Jak3, Lck and Syk are known to participate in IL-2-mediated intracellular signal transduction. Jak1, Lck and Syk are associated with the cytoplasmic domain of the beta chain, whereas Jak3 is associated with the cytoplasmic domain of the gamma chain, which is shared among receptors for IL-2, IL-4, IL-7 and IL-15. We first demonstrated that Jak1 is associated with the alpha chains of receptors for IL-4, IL-7 and IL-15 as well as the IL-2 receptor beta chain. Furthermore, we revealed that two proline residues in the box1 region, which is conserved in the IL-2 receptor beta chain and the alpha chains of the cytokine receptors, are essentially involved in association with Jak1. The MOLT4 transfectants with the box1 mutants of the IL-2 receptor beta chain lacking Jak1 association showed IL-2 responsiveness, in terms of activations of Jak3 and Stat5 and induction of cell growth, indicating that Jak1 is dispensable for IL-2-mediated cell growth signaling, and that Jak1 activation is not required for activation of Jak3 and Stat5 in the MOLT4 transfectants.
Leukemia 1997 Apr
PMID:Regulation of IL-2 signaling. 920 10

We have characterized the cDNA of MZFM, the mouse homolog to the novel human putative tumor suppressor gene ZFM1. The total length of the cDNA is 2,637 nucleotides with an open reading frame for a protein of 548 amino acids containing 4.7% methionine and 17.2% proline. The predicted molecular mass of 59 kD fits the 62-kD band experimentally determined by NaDodSO4-PAGE from in vitro translation products of in vitro-transcribed MZFM cDNA. The MZFM cDNA best matches to that ZFM1-isoform without the so-called 0.25-kb E-domain and to the L49345 cDNA recently identified in a human leukemia cell line. Northern analysis reveals expression of MZFM only in spleen macrophages. Reverse transcription polymerase chain reaction (RT-PCR) in combination with Southern analysis also detects a low basal expression in splenic T cells and B cells, as well as in other tissues such as heart, kidney, brain, liver, testis, bone marrow, adrenal gland, lymph nodes, pancreas, and thymus. In splenic macrophages, MZFM mRNA is alternatively spliced yielding a 3.6-kb transcript with E-domain, a 3.0-kb transcript without E-domain, and a 2.7-kb transcript with E-domain. The predicted MZFM protein contains diverse functional domains, i.e., a nuclear localization signal, a metal binding motif, a glutamine/proline stretch, proline-clusters, a CGA-motif, and a QUA1-KH-QUA2 region, thus indicating multiple functions of MZFM. Presumably, MZFM is a new member of those proteins combining features of signal transduction and RNA activation (STAR-proteins). The different MZFM-isoforms may be part of a macrophage-inherent program of transduction of environmental signals into different activational states of macrophages.
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PMID:Enhanced expression in spleen macrophages of the mouse homolog to the human putative tumor suppressor gene ZFM1. 921 69

HTLV-I is an oncogenic retrovirus that is associated with adult T-cell leukemia. HTLV-I protease and HTLV-I protease fused to a deca-histidine containing leader peptide (His-protease) have been cloned, expressed, and purified. The refolded proteases were active and exhibited nearly identical enzymatic activities. To begin to characterize the specificity of HTLV-I, we measured protease cleavage of peptide substrates and inhibition by protease inhibitors. HTLV-I protease cleavage of a peptide representing the HTLV-I retroviral processing site P19/24 (APQVLPVMHPHG) yielded Km and kcat values of 470 microM and 0.184 s-1 while cleavage of a peptide representing the processing site P24/15 (KTKVLVVQPK) yielded Km and kcat values of 310 microM and 0.0060 s-1. When the P1' proline of P19/24 was replaced with p-nitro-phenylalanine (Nph), the ability of HTLV-I protease to cleave the substrate (APQVLNphVMHPL) was improved. Inhibition of HTLV-I protease and His-protease by a series of protease inhibitors was also tested. It was found that the Ki values for inhibition of HTLV-I protease and His-protease by a series of pepsin inhibitors ranged from 7 nM to 10 microM, while the Ki values of a series of HIV-1 protease inhibitors ranged from 6 nM to 127 microM. In comparison, the Ki values for inhibition of pepsin by the pepsin inhibitors ranged from 0.72 to 19.2 nM, and the Ki values for inhibition of HIV-1 protease by the HIV protease inhibitors ranged from 0.24 nM to 1.0 microM. The data suggested that the substrate binding site of HTLV-I protease is different from the substrate binding sites of pepsin and HIV-1 protease, and that currently employed HIV-1 protease inhibitors would not be effective for the treatment of HTLV-I infections.
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PMID:Substrates and inhibitors of human T-cell leukemia virus type I protease. 986 Aug 66

The surface proteins (SU) of murine type-C retroviruses have a central hypervariable domain devoid of cysteine and rich in proline. This 41-amino-acid region of Friend ecotropic murine leukemia virus SU was shown to be highly tolerant of insertions and deletions. Viruses in which either the N-terminal 30 amino acids or the C-terminal 22 amino acids of this region were replaced by the 7-amino-acid sequence ASAVAGA were fully infectious. Insertions of this 7-amino-acid sequence at the N terminus, center, and the C terminus of the hypervariable domain had little effect on envelope protein (Env) function, while this insertion at a position 10 amino acids following the N terminus partially destabilized the association between the SU and transmembrane subunits of Env. Large, complex domains (either a 252-amino-acid single-chain antibody binding domain [scFv] or a 96-amino-acid V1/V2 domain of HIV-1 SU containing eight N-linked glycosylation sites and two disulfides) did not interfere with Env function when inserted in the center or C-terminal portions of the hypervariable domain. The scFv domain inserted into the C-terminal region of the hypervariable domain was shown to mediate binding of antigen to viral particles, demonstrating that it folded into the active conformation and was displayed on the surface of the virion. Both positive and negative enrichment of virions expressing the V1/V2 sequence were achieved by using a monoclonal antibody specific for a conformational epitope presented by the inserted sequence. These results indicated that the hypervariable domain of Friend ecotropic SU does not contain any specific sequence or structure that is essential for Env function and demonstrated that insertions into this domain can be used to extend particle display methodologies to complex protein domains that require expression in eukaryotic cells for glycosylation and proper folding.
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PMID:The hypervariable domain of the murine leukemia virus surface protein tolerates large insertions and deletions, enabling development of a retroviral particle display system. 997 57

The c-myb oncogene has been a target of retroviral insertional mutagenesis in murine monocytic leukemias. One mechanism by which c-myb can be activated is through the integration of a retroviral provirus into the central portion of the locus, causing premature termination of c-myb transcription and translation. We had previously shown that a leukemia-specific c-Myb protein, truncated at the site of proviral integration by 248 amino acids, had approximately a fourfold-increased half-life compared to the normal c-Myb protein, due to its ability to escape rapid degradation by the ubiquitin-26S proteasome pathway. Here we provide evidence for the existence of more than one instability determinant in the carboxy-terminal region of the wild-type protein, which appear to act independently of each other. The data were derived from examination of premature termination mutants and deletion mutants of the normal protein, as well as analysis of another carboxy-terminally truncated protein expressed in leukemia. Evidence is provided that one instability determinant is located in the terminal 87 amino acids of the protein and another is located in the vicinity of the internal region that has leucine zipper homology. In leukemias, different degrees of protein stability are attained following proviral integration depending upon how many determinants are removed. Interestingly, although PEST sequences (rich in proline, glutamine, serine, and threonine), often associated with degradation, are found in c-Myb, deletion of PEST-containing regions had no effect on protein turnover. This study provides further insight into how inappropriate expression of c-Myb may contribute to leukemogenesis. In addition, it will facilitate further studies aimed at characterizing the specific role of individual regions of the normal protein in targeting to the 26S proteasome.
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PMID:Identification of protein instability determinants in the carboxy-terminal region of c-Myb removed as a result of retroviral integration in murine monocytic leukemias. 997 84


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