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)

Evaluation of the efficiency of immunizations with syngeneic tumor vaccines prepared from cells treated with cholesterol hemisuccinate (CHS) was performed in five animal models: P815 mastocytoma in DBA/2 mice, MCA-103 fibrosarcoma in C57BL/6N mice, L1210 leukemia in DBA/2 mice, Ehrlich ascites carcinoma in C57BL/6N mice, and CBP pancreatic cancer in CB/SsLak hamsters. Animals received two to four weekly intraperitoneal immunizations with 10(6) or 10(7) tumor cells, followed by challenges with syngeneic viable tumor cells. Survival and tumor growth rates were observed. No significant differences were observed among animals immunized with CHS-treated irradiated tumor vaccines, nontreated irradiated tumor vaccines, and nonimmunized controls in the P815, MCA-103, L1210, and CBP models. Mice immunized with nontreated irradiated Ehrlich ascites cell vaccines showed longer survival than those immunized with CHS-treated irradiated cell vaccines and nonimmunized controls. Results indicated that CHS-treated tumor cell vaccines were not effective in protecting against tumor challenges in five different syngeneic tumor models.
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PMID:Experiments evaluating antitumor immunity induced by cholesterol hemisuccinate-treated syngeneic cell vaccines. 377 33

The human T-cell leukemia virus type I (HTLV-I) transactivator protein Tax is critical for the activation of viral gene expression and the transformation of T-lymphocytes. Tax activation of HTLV-I gene expression is mediated by three highly homologous regulatory elements known as 21 bp repeats which bind the transcription factor CREB. Questions remain about the mechanism by which Tax can stimulate CREB binding, whether Tax alters CREB binding affinity, what specific sequences in the HTLV-I 21 bp repeat mediate ternary complex formation, and if the ternary complex comprised of Tax and CREB can recruit coactivators such as CBP. To address these points, we used immobilized templates containing either the HTLV-I 21 bp repeats or the somatostatin CRE to assay Tax association with ATF/CREB family members. Tax formed a stable ternary complex on each of the 21 bp repeats with the transcription factor CREB but not related ATF/CREB proteins. In contrast, Tax did not form a similar complex on the CREB binding site in the somatostatin promoter. The formation of this complex was dependent on 3' sequences flanking the CREB binding site within each of the 21 bp repeats and resulted in marked increases in CREB association and binding affinity. Tax increased the binding of phosphorylated CREB to the 21 bp repeat resulting in increased association of the coactivator CBP. However, Tax did not form a complex on the somatostatin CRE in the presence of either phosphorylated or non-phosphorylated CREB and it did not stimulate CBP association to this element. These studies extend previous work and demonstrate how specific DNA sequences flanking the CREB binding site regulate the formation of a stable ternary complex that is able to more efficiently recruit the coactivator CBP.
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PMID:HTLV-1 21 bp repeat sequences facilitate stable association between Tax and CREB to increase CREB binding affinity. 895 Feb 64

The involvement of 11q23-balanced translocations in acute leukemia after treatment with drugs that inhibit the function of DNA topoisomerase II (topo II) is being recognized with increasing frequency. We and others have shown that the gene at 11q23 that is involved in all of these treatment-related leukemias is MLL (also called ALL1, Htrx, and HRX). In general, the translocations in these leukemias are the same as those occurring in de novo leukemia [eg, t(9;11), t(11;19), and t(4;11)], with the treatment-related leukemias accounting for no more than 5% to 10% of any particular translocation type. We have cloned the t(11;16)(q23;p13.3) and have shown that it involves MLL and CBP (CREB binding protein). The CBP gene was recently identified as a partner gene in the t(8;16) that occurs in acute myelomonocytic leukemia (AML-M4) de novo and rarely in treatment-related acute myeloid leukemia. We have studied eight t(11;16) patients, all of whom had prior therapy with drugs targetting topo II with fluorescence in situ hybridization (FISH) using a probe for MLL and a cosmid contig covering the CBP gene. Both probes were split in all eight patients and the two derivative (der) chromosomes were each labeled with both probes. Use of an approximately 100-kb PAC located at the breakpoint of chromosome 16 from one patient revealed some variability in the breakpoint because it was on the der(16) in three patients, on the der(11) in another, and split in four others. We assume that the critical fusion gene is 5'MLL/3'CBP. Our series of patients is unusual because three of them presented with a myelodysplastic syndrome (MDS) most similar to chronic myelomonocytic leukemia (CMMoL) and one other had dyserythropoiesis; MDS is rarely seen in 11q23 translocations either de novo or with t-AML. Using FISH and these same probes to analyze the lineage of bone marrow cells from one patient with CMMoL, we showed that all the mature monocytes contained the fusion genes as did some of the granulocytes and erythroblasts; none of the lymphocytes contained the fusion gene. The function of MLL is not well understood, but many domains could target the MLL protein to particular chromatin complexes. CBP is an adapter protein that is involved in regulating transcription. It is also involved in histone acetylation, which is thought to contribute to an increased level of gene expression. The fusion gene could alter the CBP protein such that it is constitutively active; alternatively, it could modify the chromatin-association functions of MLL.
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PMID:All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. 922 52

The recurring translocation t(11;16)(q23;p13.3) has been documented only in cases of acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II. We show that the MLL gene is fused to the gene that codes for CBP (CREB-binding protein), the protein that binds specifically to the DNA-binding protein CREB (cAMP response element-binding protein) in this translocation. MLL is fused in-frame to a different exon of CBP in two patients producing chimeric proteins containing the AT-hooks, methyltransferase homology domain, and transcriptional repression domain of MLL fused to the CREB binding domain or to the bromodomain of CBP. Both fusion products retain the histone acetyltransferase domain of CBP and may lead to leukemia by promoting histone acetylation of genomic regions targeted by the MLL AT-hooks, leading to transcriptional deregulation via aberrant chromatin organization. CBP is the first partner gene of MLL containing well defined structural and functional motifs that provide unique insights into the potential mechanisms by which these translocations contribute to leukemogenesis.
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PMID:MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). 923 46

Two distinct leukemia syndromes are associated with abnormalities of chromosome band 8p11. First, a myeloproliferative disorder with features characteristic of both chronic myeloid leukemia and non-Hodgkin's lymphoma and second, an acute myeloid leukemia (AML) with French-American-British (FAB) M4/5 morphology and prominent erythrophagocytosis. The two syndromes are exemplified by a t(8;13)(p11;q12) and a t(8;16)(p11;p13), respectively, but cytogenetic variants of both have been described. Recently, the t(8;16) has been cloned and shown to fuse the MOZ gene at 8p11 to the CBP gene at 16p13. We have used fluorescence in situ hybridization (FISH), Southern blotting, and reverse transcriptase-polymerase chain reaction (RT-PCR) to refine the 8p11 breakpoint in three cases with t(8;13)(p11;q12) and in a single case of AML-M5 with a clinical picture apparently identical to that found in patients with a t(8;16), but characterized by an inv(8)(p11q13). FISH analysis was performed with several 8p11 CEPH yeast artificial chromosome (YAC) clones. YAC 782H11 was centromeric to the one case with t(8;13) tested, but was telomeric to the inv(8). YAC 847B12 was telomeric to both the t(8;13) and the inv(8), whereas YAC 829D12 was centromeric to the t(8;13), but split by the inv(8). Southern blotting and PCR of YAC 829D12 showed that it contained the MOZ gene. A 900-bp MOZ fragment encompassing the published t(8;16) breakpoint was amplified by PCR from normal peripheral blood leukocyte cDNA and used to probe Southern blots of patient DNA. A rearrangement was detected in the case with inv(8), but not in any of the three cases with t(8;13). Southern blotting with a CBP probe and RT-PCR with MOZ and CBP primers suggested that the inv(8) does not result in a cryptic MOZ-CBP fusion. It is likely, therefore, that MOZ is fused to a novel gene at 8q13 in this case. We conclude that the t(8;13) breakpoint is flanked by YACs 782H11 and 847B12 and is at least 1 Mb telomeric to MOZ. MOZ is involved, however, in a new variant of the t(8;16).
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PMID:Abnormalities of chromosome band 8p11 in leukemia: two clinical syndromes can be distinguished on the basis of MOZ involvement. 937 94

Chromosomal abnormalities of band 8p11 are associated with a distinct subtype of acute myeloid leukemia with French-American-British M4/5 morphology and prominent erythrophagocytosis by the blast cells. This subtype is usually associated with the t(8;16)(p11;p13), a translocation that has recently been shown to result in a fusion between the MOZ and CBP genes. We have cloned the inv(8)(p11q13), an abnormality associated with the same leukemia phenotype, and found a novel fusion between MOZ and the nuclear receptor transcriptional coactivator TIF2/GRIP-1/NCoA-2. This gene has not previously been implicated in the pathogenesis of leukemia or other malignancies. MOZ-TIF2 retains the histone acetyltransferase homology domains of both proteins and also the CBP binding domain of TIF2. We speculate that the apparently identical leukemia cell phenotype observed in cases with the t(8;16) and the inv(8) arises by recruitment of CBP by MOZ-TIF2, resulting in modulation of the transcriptional activity of target genes by a mechanism involving abnormal histone acetylation.
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PMID:A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. 955 66

CBP and its homolog p300 are large nuclear molecules that coordinate a variety of transcriptional pathways with chromatin remodeling. They interact with transcriptional activators as well as repressors, direct chromatin-mediated transcription, function in TP53-mediated apoptosis, and participate in terminal differentiation of certain tissue types. Recent evidence suggests that the demand for CBP/p300 is greater than the supply, and that competition for CBP/p300 might play an important role in cell growth regulation. Alterations of the human CBP gene have been implicated in hematological malignancies as well as in congenital malformation and mental retardation. Likewise, the p300 gene has been recently implicated in leukemia and mutations in both alleles have been observed in gastric and colorectal carcinomas. The role of these proteins in human disease coupled with biochemical evidence suggests that CBP and p300 are tumor suppressor proteins essential in cell-cycle control, cellular differentiation and human development.
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PMID:Conjunction dysfunction: CBP/p300 in human disease. 961 1

The oncoprotein Tax, encoded by the human T-cell leukemia virus type I (HTLV-I), is required for high-level viral transcription and is strongly linked to HTLV-I-associated malignant transformation. Recent evidence suggests that Tax stimulates HTLV-I transcription through recruitment of the cellular coactivator protein CBP to the HTLV-I promoter, promoting high-level viral replication via the transcriptional activation properties associated with CBP. Tax directly contacts the KIX domain of CBP to stably anchor the coactivator to nucleoprotein complexes at the promoter. Here, we identify KIX amino acid residues 588 to 683 as the minimal region sufficient for interaction with Tax. This region is similar to the minimal KIX amino acid residues necessary for strong interaction with phosphorylated CREB, and is composed of a structural domain that forms an extensive hydrophobic core. We further show that a double point mutation in KIX differentially affects the binding of Tax and phosphorylated CREB, suggesting that these transcription factors may recognize unique amino acid residues within the KIX domain. These observations suggest that Tax directly contacts the hydrophobic core of KIX, and provides a structural framework to further define the molecular interactions between Tax and CBP.
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PMID:Molecular interactions between the coactivator CBP and the human T-cell leukemia virus Tax protein. 969 55

The human T-cell leukemia virus type I or HTLV-I is the causative agent of adult T-cell leukemia. A protein encoded by HTLV-I, Tax, activates viral gene expression and is essential for transforming T-lymphocytes. Tax activates HTLV-I gene expression via interactions with the ATF/CREB proteins and the coactivators CBP/p300 which assemble as a multiprotein complex on regulatory elements known as 21-bp repeats in the HTLV-I LTR. Tax can also activate expression from cellular genes including the interleukin-2 (IL-2) and the IL-2 receptor genes via increases in nuclear levels of NF-kappaB. Tax modulation of gene expression via the ATF/CREB and NF-kappaB pathways is linked to its transforming properties. This review discusses the mechanisms by which Tax regulates viral and cellular gene expression.
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PMID:Regulation of gene expression by HTLV-I Tax protein. 977 18

Tax protein of human T-cell leukemia virus type 1 (HTLV-1) is a potent transcriptional regulator which can activate or repress specific cellular genes and has been proposed to contribute to leukemogenic processes in adult T-cell leukemia. The molecular mechanism of Tax-mediated trans-activation has been well investigated. However, trans-repression by Tax remains to be studied in detail, although it is known to require a specific DNA element such as E-box or p53 binding site. Examining possible mechanisms of trans-repression, we found that co-expression of E47 and p300 activated E-box dependent transcription and this activation was efficiently repressed by Tax. In this system, Tax bound to p300 and decreased the level of p300 complexed on the E-box element. Similarly, Tax inhibited transcription directed by p53 and CBP, reducing the level of CBP on the p53 binding site. These results indicate that Tax interferes with recruitment of CBP/p300 into protein complexes on E-box and p53 binding site through its binding to CBP/p300. In contrast to these findings, we observed that Tax increased the level of CBP on the viral 21-bp enhancer which is trans-activated by Tax. From these observations, we propose a universal mechanism for Tax-mediated trans-repression and trans-activation of transcription in which Tax binds to CBP/p300 and determines the accessibility of CBP/p300 to protein complexes on specific DNA element.
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PMID:Tax protein of HTLV-1 inhibits CBP/p300-mediated transcription by interfering with recruitment of CBP/p300 onto DNA element of E-box or p53 binding site. 1043 95


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