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 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

CREB binding protein (CBP) is a cellular coactivator protein that regulates essentially all known pathways of gene expression. The transcriptional coactivator properties of CBP are utilized by at least 25 different transcription factors representing nearly all known classes of DNA binding proteins. Once bound to their target genes, these transcription factors are believed to tether CBP to the promoter, leading to activated transcription. CBP functions to stimulate transcription through direct recruitment of the general transcription machinery as well as acetylation of both histone and transcription factor substrates. Recent observations indicate that a critical dosage of CBP is required for normal development and tumor suppression, and that perturbations in CBP concentrations may disrupt cellular homeostasis. Furthermore, there is accumulating evidence that CBP deregulation plays a direct role in hematopoietic malignancies. However, the molecular events linking CBP deregulation and malignant transformation are unclear. Further insight into the function of CBP, and its role as a tumor suppressor, can be gained through recent studies of the human T-cell leukemia virus, type I (HTLV-I) Tax oncoprotein. Tax is known to utilize CBP to stimulate transcription from the viral promoter. However, recent data suggest that as a consequence of the Tax-CBP interaction, many cellular transcription factor pathways may be deregulated. Tax disruption of CBP function may play a key role in transformation of the HTLV-I-infected cell. Thus, Tax derailment of CBP may lend important information about the tumor suppressor properties of CBP and serve as a model for the role of CBP in hematopoietic malignancies.
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PMID:Insight into the tumor suppressor function of CBP through the viral oncoprotein tax. 1109 23

Promyelocytic leukemia (PML) oncogenic domains (PODs) accumulate the transcriptional cofactor named CREB binding protein (CBP) and have been suggested to function as centers of transcription. Transcriptional activation by nuclear hormones, such as glucocorticoids, is augmented by the key constituent of PODs, the PML protein, and decreased by the POD-associated Tax protein of human T-cell leukemia virus type 1 (HTLV-1). This led to the hypothesis that intact PODs might play a positive role in the activation of these promoters. We report here that transiently expressed E4orf3 protein of adenovirus type 5, immediate-early protein 1 of human cytomegalovirus, and the PML-retinoic acid receptor fusion protein from leukemia cells each redistribute CBP within the nucleus. However, unlike the Tax protein of HTLV-1, these factors did not inhibit a glucocorticoid-inducible promoter but strongly enhanced its activity. Thus, at least glucocorticoid-induced transcription does not depend on POD integrity.
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PMID:Viral and cellular factors that target the promyelocytic leukemia oncogenic domains strongly activate a glucocorticoid-responsive promoter. 1133 23

The in-frame fusion of mixed lineage leukemia to CREB binding protein has been cloned from several patients with t-acute myeloid leukemia and a t(11;16)(q23;p13). A murine retroviral transduction model of mixed lineage leukemia fused to CREB binding protein successfully recapitulates the disease. Interestingly, the mice also develop a preleukemic phase reminiscent of what is often seen in patients with t(11;16). From this work, it was determined that minimally, the amino terminus of mixed lineage leukemia fused to the bromodomain and histone acetyltransferase domain of CREB binding protein are necessary for developing acute myeloid leukemia. This model provides a useful tool for understanding the biologic basis of mixed lineage leukemia leukemogenesis and for developing and testing potential therapeutic agents.
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PMID:Retroviral transduction model of mixed lineage leukemia fused to CREB binding protein. 1156 Nov 59

The promyelocytic leukaemia (PML) gene, which encodes a transformation and growth suppressor, was found to regulate transcription and apoptosis. PML was first identified at the chromosomal translocation break-points t(15;17) of acute promyelocytic leukaemia and the gene product may mediate cell-cycle control and apoptosis. PML was found to interact with the co-transactivator CREB binding protein (CBP) and the apoptotic-modulator Bax. To determine if PML, CBP and Bax may be involved in solid tumours, such as the nasopharyngeal carcinoma (NPC), a rare neoplasia that is prevalent in Southern China, the expression of these proteins and the proliferation marker Ki-67 was analysed by immunohistochemical staining. Expression of PML in the PML-oncogenic domain (POD) or nuclear bodies in most NPC was inversely correlated with the expression of Ki-67. In addition, based on PML expression patterns in NPC three subtypes could be identified, namely, Subtype-1, with strong PML expression in POD structures and with low Ki-67 staining; Subtype-2, where PML was expressed in a homogeneously diffused pattern, but with a low intensity in the tumour cells; while Ki-67 was expressed in a moderate number of cells and Subtype-3, where the majority of tumour cells were PML-negative, while a considerable number of tumour cells were strongly labelled with Ki-67. Furthermore, CBP was present in most of the NPC cells with moderate-strong nuclear staining, while the expression in non-tumour cells were relatively weak. However, there was no direct correlation between PML and CBP expression in the NPC examined. In addition, there was low or no expression of Bax in the NP and NPC. This is, to our knowledge, the first report describing PML and CBP expression in NPC and our data strongly suggests that PML and CBP, but not Bax, may play a role in the transformed phenotypes of NPC.
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PMID:Differential expression of the suppressor PML and Ki-67 identifies three subtypes of human nasopharyngeal carcinoma. 1214 48

We previously reported, both in transfected cells and in human T-cell leukemia virus type-2 subtype B infected cells, that the viral transactivator Tax-2B protein could inhibit p53 functions. We have now investigated the mechanism through which Tax-2B represses p53 using GFPTax-2B fusion proteins. We present evidence that Tax-2B inhibition of p53 function is not linked to CREB/ATF activation, but is uniquely correlated with the interaction of CREB binding protein (CBP), but not p300, with the C-terminus of Tax-2B. Wild type, but not a Tax-2B-M47 mutant, inhibits p53 function in adherent cells. We demonstrate that both Tax-2B and Tax-2B-M47 can bind p300, while Tax-2B-M47 is impaired for CBP binding. Importantly, transfection of increasing amounts of CBP but not p300 or p300/CBP-associated factor (P/CAF) could rescue p53 transcriptional activity in the presence of Tax-2B in nonlymphocytic cells. In lymphoid cells, Tax-2B mediated inhibition of p53 is correlated with the NF-kappaB pathway activation and could be prevented by the overexpression of an IkappaBalpha mutant. Given the similarities between the functional domains of CBP and p300, these results are intriguing and suggest that Tax-2B must bind the CR2 domain of CBP, but not that of p300 in order to repress p53.
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PMID:Utilization of the CBP but not the p300 co-activator by human T-lymphotropic virus type-2 Tax for p53 inhibition. 1515 94

The calcium-responsive transactivator (CREST) is required for the normal development of neuronal dendritic trees. Here we report that CREST is localized to sub-nuclear structures in the rat neuroendocrine pheochromocytoma PC12 cells. A yellow fluorescence protein-CREST fusion protein was expressed in HEK 293 and PC12 cells and the recombinant protein was exclusively targeted to nuclear bodies. A similar result was obtained with a Flag-tagged CREST. Deleting the N-terminal 148 or the C-terminal 79 amino acid sequences had no effect on targeting, whereas removing 164 amino acid residues from the C-terminus abolished nuclear body localization. We found that CREST did not co-localize with promyelocytic leukaemia oncoprotein (PML) body and was not targeted to PML bodies. Overexpression of CREST markedly increased the number of nuclear bodies positive for the histone acetyltransferase CREB binding protein (CBP). Double immunofluorescence staining of Flag-CREST and CBP suggested that CREST and CBP had a high degree of co-localization within the nuclear bodies. Deletion of the CBP binding domain of CREST inhibited the recruitment of CBP to CREST nuclear bodies. These results suggest that CBP recruitment to nuclear bodies by CREST may play an important role in CREST-mediated calcium-responsive transactivation, and CREST nuclear body may function as an assembly site for activators/co-activators in gene transcription control.
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PMID:The calcium-responsive transactivator recruits CREB binding protein to nuclear bodies. 1548 21

Regulation of transcription requires interactions between transcriptional activators and transcriptional co-activator CREB binding protein (CBP). The KIX domain of CBP can bind simultaneously to two different proteins, providing an additional mechanism for transcriptional regulation. Here we describe the solution structure of the ternary complex formed by cooperative binding of activation domains from the c-Myb and mixed lineage leukemia (MLL) transcription factors to the KIX domain. The MLL and c-Myb domains form helices that bind to two distinct hydrophobic grooves on opposite faces of KIX. Compared to the binary KIX:c-Myb complex, significant changes are observed in the structure of KIX at the MLL binding interface in the ternary complex. Two regions of KIX that are disordered in the binary complex become structured in the ternary complex: a flexible loop forms intimate contacts with bound MLL, and the C-terminal helix is extended and stabilized by MLL binding. This structural change results in the formation of additional electrostatic/polar interactions between KIX and the bound c-Myb, providing a structural basis for the cooperativity observed for the ternary complex.
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PMID:Structural basis for cooperative transcription factor binding to the CBP coactivator. 1625 72

Curcumin, the active chemical of the Asian spice turmeric, exhibits anticancer activity in several human cancer cell lines. We previously have proved that curcumin was a new member of the histone deacetylases (HDAC) inhibitors, while constitutive nuclear factor kappa B (NF-kappaB) is believed to be a crucial event for enhanced proliferation and survival of malignant cells. Here, we investigate the effect of curcumin on the activation of NF-kappaB signal molecule in Raji cells to explore its relationship with HDACs or p300/CREB binding protein (CBP). Curcumin presented striking proliferation inhibition potency on Raji cells in vitro, with the IC(50) value for 24 hr being 25 micromol/l. Significant decreases in the amounts of p300, HDAC1 and HDAC3 were detected after treatment with curcumin. These suppressing effects were more pronounced when the administered dose increased. The protection degradation of HDAC1 and p300 by MG-132 could be partially reversed by curcumin. Furthermore, curcumin could also prevent degradation of I kappaB alpha and inhibit nuclear translocation of the NF-kappaB/p65 subunit, as well as expression of Notch 1, induced by tumour necrosis factor-alpha. The results suggest that the depressive effect of curcumin on NF-kappaB signal transduction pathway may be mediated via the various components of the HDACs and p300/Notch 1 signal molecules, and may represent a new remedy for acute leukaemia.
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PMID:Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells. 1792 89

B cell chronic lymphocytic leukemia (B-CLL) is the most common human leukemia. Deregulation of the T cell leukemia/lymphoma 1 (TCL1) oncogene in mouse B cells causes a CD5-positive leukemia similar to aggressive human B-CLLs. To examine the mechanisms by which Tcl1 protein exerts oncogenic activity in B cells, we investigated the effect of Tcl1 expression on NF-kappaB and activator protein 1 (AP-1) activity. We found that Tcl1 physically interacts with c-Jun, JunB, and c-Fos and inhibits AP-1 transcriptional activity. Additionally, Tcl1 activates NF-kappaB by physically interacting with p300/CREB binding protein. We then sequenced the TCL1 gene in 600 B-CLL samples and found 2 heterozygous mutations: T38I and R52H. Importantly, both mutants showed gain of function as AP-1 inhibitors. The results indicate that Tcl1 overexpression causes B-CLL by directly enhancing NF-kappaB activity and inhibiting AP-1.
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PMID:Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL. 1906 21


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