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)

Adult T-cell leukemia (ATL) is an aggressive hematologic malignancy caused by human T-cell leukemia virus type I (HTLV-1). Tax, encoded by the HTLV-1 pX region, has been recognized by its pleiotropic actions to play a critical role in leukemogenesis. Three highly conserved 21-bp repeat elements located within the long terminal repeat, commonly referred to as Tax-responsive element 1 (TRE-1), are critical to Tax-mediated viral transcriptional activation through complex interaction with cyclic AMP-responsive element binding protein (CREB), CBP/p300 and PCAF. Tax has also been shown to activate transcription from a number of critical cellular genes through the NF-kappaB and serum-responsive factor pathways. Tax transactivation has been attributed to the protein's interaction with transcription factors, chromatin remodeling complexes, cell cycle and repair genes. In this review, we will discuss some of the latest findings on this fascinating viral activator and highlight its regulation of cellular factors including CREB, p300/CBP and their effect on RNA polymerase II and chromatin remodeling, as well as its role in cytoplasmic and nuclear function. We will highlight the possible contribution of each factor, discuss Tax's critical peptide domains and highlight its post-transcriptional modifications. It is quite obvious that, collectively, Tax's effects on a wide variety of cellular targets cooperate in promoting cell proliferation and leukemogenesis. In addition, the post-transcriptional effects of Rex play an important role in virus replication. Understanding these interactions at a molecular level will facilitate the targeted development of drugs to effectively inhibit or treat ATL.
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PMID:Transcriptional and post-transcriptional gene regulation of HTLV-1. 1615 1

Human T-cell leukemia virus and simian T-cell leukemia virus (STLV) form the primate T-cell lymphotropic viruses group. Human T-cell leukemia virus type 1 and type 2 (HTLV-1 and HTLV-2) encode the Tax viral transactivator (Tax1 and Tax2, respectively). Tax1 possesses an oncogenic potential and is responsible for cell transformation both in vivo and in vitro. We and others have recently discovered the existence of human T-cell lymphotropic virus type 3. However, there is currently no evidence for the presence of a Tax protein in HTLV-3-infected individuals. We show that the serum of an HTLV-3 asymptomatic carrier and the sera of two STLV-3-infected monkeys contain specific anti-Tax3 antibodies. We also show that tax3 mRNA is present in the PBMCs obtained from an STLV-3-infected monkey, demonstrating that Tax3 is expressed in vivo. We further demonstrate that Tax3 intracellular localization is very similar to that of Tax1 and that Tax3 binds to both CBP and p300 coactivators. Using purified Tax3, we show that the protein increases transcription from a 4TxRE G-free cassette plasmid in an in vitro transcription assay. In all cell types tested, including transiently transfected lymphocytes, Tax3 activates its own promoter STLV-3 long terminal repeat (LTR), which contains only two Tax Responsive Elements (TREs), and activates also HTLV-1 and HTLV-2 LTRs. In addition, Tax3 also activates the NF-kappaB pathway. We also show that Tax3 possesses a PDZ-binding sequence at its C-terminal end. Our results demonstrate that Tax3 is a transactivator, and that its properties are more similar to that of Tax1, rather than of Tax2. This suggests the possible occurrence of lymphoproliferative disorders among HTLV-3-infected populations.
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PMID:The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax. 1653 31

Upon infection of human T-cell leukemia virus type 1 (HTLV-1), the provirus is integrated into the host cell genome and subsequently packaged into chromatin that contains histone H1. Consequently, transcriptional activation of the virus requires overcoming the environment of chromatin and H1. To efficiently activate transcription, HTLV-1 requires the virally encoded protein Tax and cellular transcription factor CREB. Together Tax and CREB interact with three cis-acting promoter elements called viral cyclic-AMP response elements (vCREs). Binding of Tax and CREB to the vCREs promotes association of p300/CBP into the complex and leads to transcriptional activation. Therefore, to fully understand the mechanism of Tax transactivation, it is necessary to examine transcriptional activation from chromatin assembled with H1. Using a DNA template harboring the complete HTLV-1 promoter sequence and a highly defined recombinant assembly system, we demonstrate proper incorporation of histone H1 into chromatin. Addition of H1 to the chromatin template reduces HTLV-1 transcriptional activation through a novel mechanism. Specifically, H1 does not inhibit CREB or Tax binding to the vCREs or p300 recruitment to the promoter. Rather, H1 directly targets p300 acetyltransferase activity. Interestingly, in determining the mechanism of H1 repression, we have discovered a previously undefined function of Tax, overcoming the repressive effects of H1-chromatin. Tax specifically abrogates the H1 repression of p300 enzymatic activity in a manner independent of p300 recruitment and without displacement of H1 from the promoter.
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PMID:Tax abolishes histone H1 repression of p300 acetyltransferase activity at the human T-cell leukemia virus type 1 promoter. 1694 93

HATs (histone acetyltransferases) contribute to the regulation of gene expression, and loss or dysregulation of these activities may link to tumorigenesis. Here, we demonstrate that expression levels of HATs, p300 and CBP [CREB (cAMP-response-element-binding protein)-binding protein] were decreased during chemical hepatocarcinogenesis, whereas expression of MOZ (monocytic leukaemia zinc-finger protein; MYST3)--a member of the MYST [MOZ, Ybf2/Sas3, Sas2 and TIP60 (Tat-interacting protein, 60 kDa)] acetyltransferase family--was induced. Although the MOZ gene frequently is rearranged in leukaemia, we were unable to detect MOZ rearrangement in livers with hyperplastic nodules. We examined the effect of MOZ on hepatocarcinogenic-specific gene expression. GSTP (glutathione S-transferase placental form) is a Phase II detoxification enzyme and a well-known tumour marker that is specifically elevated during hepatocarcinogenesis. GSTP gene activation is regulated mainly by the GPE1 (GSTP enhancer 1) enhancer element, which is recognized by the Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2)-MafK heterodimer. We found that MOZ enhances GSTP promoter activity through GPE1 and acts as a co-activator of the Nrf2-MafK heterodimer. Further, exogenous MOZ induced GSTP expression in rat hepatoma H4IIE cells. These results suggest that during early hepatocarcinogenesis, aberrantly expressed MOZ may induce GSTP expression through the Nrf2-mediated pathway.
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PMID:Histone acetyltransferase MOZ acts as a co-activator of Nrf2-MafK and induces tumour marker gene expression during hepatocarcinogenesis. 1708 29

The promyelocytic leukaemia gene (Pml) is a tumor suppressor identified in acute promyelocytic leukaemia (APL), where it is fused to RAR alpha gene as a result of the chromosomal translocation t(15;17). Pml encodes both nuclear and cytoplasmic isoforms. While nuclear PML has been intensively investigated, cytoplasmic PML proteins are less characterized. PML nuclear isoforms (nPML) are the essential components of subnuclear structures referred to as PML nuclear bodies (PML-NB). In response to cellular insults such as DNA damage and oncogenic activation, nPML modulates p53 activity through CBP-mediated acetylation and activates its pro-apoptotic and growth suppressive functions. Two missense mutations resulting in truncated PML cytoplasmic proteins (Mut PML) have been identified in aggressive APL cases. Here we report that cytoplasmic PML is able to induce the relocation of nPML to the cytoplasm, thus reducing the number of PML-NBs. Remarkably, Mut PML inhibits p53 transcriptional, growth suppressive, and apoptotic functions, thus suggesting that cytoplasmic expression of PML has an impact on survival through inhibition of nuclear PML. Overall our findings shed new light on the role of PML cytoplasmic proteins in the regulation of p53.
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PMID:A cytoplasmic PML mutant inhibits p53 function. 1717 28

The expression of c-myc is deregulated in Burkitt's lymphoma by the translocation t(8;14). Most of the increased c-myc expression is from the P1 promoter, which is normally a minor promoter. How the P1 promoter is activated by the immunoglobulin heavy chain gene enhancers is not understood. We identified a YY1 site in the immunoglobulin heavy-chain gene HS3 enhancer, which increased c-myc P1 promoter activity, and a MARE site, which decreased c-myc P1 activity. Small Maf proteins bound to the MARE site both in vitro and in vivo, recruited histone deacetylase 2, and resulted in deacetylation of histones H3 and H4 at the c-myc promoter region. In contrast, YY1 recruited CBP and increased histone acetylation at the c-myc promoter. Rb interacts with YY1 to prevent DNA binding in normal B cells, but no significant interaction with YY1 was detected in Burkitt's cells, and binding of YY1 to the HS3 enhancer was observed by chromatin immunoprecipitaton. Increased expression of MafK and/or decreased expression of YY1 by silencing RNA downregulated endogenous c-myc mRNA levels and increased the sensitivity of the cells to doxorubicin. Mutation of the major active sites (nuclear factor-kappa B and YY1) in the enhancers prevented c-myc activation.
Leukemia 2007 Apr
PMID:Activation of the c-myc p1 promoter in Burkitt's lymphoma by the hs3 immunoglobulin heavy-chain gene enhancer. 1728 52

Gross cytogenetic anomalies are traditionally being used as diagnostic, prognostic and therapeutic markers in the clinical management of cancer, including childhood acute lymphoblastic leukemia (ALL). Recently, it has become increasingly clear that genetic lesions driving tumorigenesis frequently occur at the submicroscopic level and, consequently, escape standard cytogenetic observations. Therefore, we profiled the genomes of 40 childhood ALLs at high resolution. We detected multiple de novo genetic lesions, including gross aneuploidies and segmental gains and losses, some of which were subtle and affected single genes. Many of these lesions involved recurrent (partially) overlapping deletions and duplications, containing various established leukemia-associated genes, such as ETV6, RUNX1 and MLL. Importantly, the most frequently affected genes were those controlling G1/S cell cycle progression (e.g. CDKN2A, CDKN1B and RB1), followed by genes associated with B-cell development. The latter group includes microdeletions of the B-lineage transcription factors PAX5, EBF, E2-2 and IKZF1 (Ikaros), as well as genes with other established roles in B-cell development, that is RAG1 and RAG2, FYN, PBEF1 or CBP/PAG. The fact that we frequently encountered multiple lesions affecting genes involved in cell cycle regulation and B-cell differentiation strongly suggests that both these processes need to be targeted independently and simultaneously to trigger ALL development.
Leukemia 2007 Jun
PMID:High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. 1744 27

Bcr-Abl-independent signaling pathways are known to be involved in imatinib resistance in some patients with chronic myelogenous leukemia (CML). In this study, to find new targets for imatinib-resistant CML displaying loss of Bcr-Abl kinase target dependence, we isolated imatinib-resistant variants, K562/R1, K562/R2, and K562/R3, which showed profound declines of Bcr-Abl levels and its tyrosine kinase activity, from K562 cells. Importantly, the imatinib resistance mechanism in these variants also included aberrant acetylation of nonhistone proteins such as p53, Ku70, and Hsp90 that was due to upregulation of histone deacetylases (HDACs) and down-regulation of histone acetyltransferase (HAT). In comparison with K562 cells, the imatinib-resistant variants showed up-regulation of HDAC1, -2, and -3 (class I HDACs) and class III SIRT1 and down-regulation of CBP/p300 and PCAF with HAT activity, and thereby p53 and cytoplasmic Ku70 were aberrantly acetylated. In addition, these were associated with down-regulation of Bax and up-regulation of Bcl-2. In contrast, the class II HDAC6 level was significantly decreased, and this was accompanied by an increase of Hsp90 acetylation in the imatinib-resistant variants, which was closely associated with loss of Bcr-Abl. These results indicate that alteration of the normal balance of HATs and HDACs leads to deregulated acetylation of Hsp90, p53, and Ku70 and thereby leads to imatinib resistance, suggesting the importance of the acetylation status of apoptosis-related nonhistone proteins in Bcr-Abl-independent imatinib resistance. We also revealed that imatinib-resistant K562 cells were more sensitive to suberoylanilide hydroxamic acid, an HDAC inhibitor, than K562 cells. These findings may have implications for HDAC as a molecular target in imatinib-resistant leukemia cells.
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PMID:Bcr-Abl-independent imatinib-resistant K562 cells show aberrant protein acetylation and increased sensitivity to histone deacetylase inhibitors. 1756 22

The viral oncoprotein Tax mediates transcriptional activation of human T-cell leukemia virus type 1 (HTLV-1). Both Tax and the cellular transcription factor CREB bind to viral cyclic AMP response elements (vCREs) located in the viral promoter. Tax and serine 133 phosphorylated CREB (pCREB) bound to the HTLV-1 promoter facilitate viral transcription via the recruitment of the large cellular coactivators CBP/p300. While the interaction between the phosphorylated kinase inducible domain (pKID) of pCREB and the KIX domain of CBP/p300 has been well characterized, the molecular interactions between KIX, full-length Tax, and pCREB have not been examined. Here we biochemically characterized the interaction between Tax and KIX in a physiologically relevant complex containing pCREB and vCRE DNA. Our data show that Tax and pCREB simultaneously and independently bind two distinct surfaces on the KIX domain: Tax binds KIX at the previously characterized mixed-lineage leukemia (MLL) protein interaction surface while pCREB binds KIX at the pKID-KIX interface. These results provide evidence for a model in which Tax and pCREB bind distinct surfaces of KIX for effective CBP/p300 recruitment to the HTLV-1 promoter. We also show that MLL competes with Tax for KIX binding, suggesting a novel mechanism of Tax oncogenesis in which normal MLL function is disrupted by Tax.
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PMID:Molecular characterization of HTLV-1 Tax interaction with the KIX domain of CBP/p300. 1770 1

SUMO (small ubiquitin-related modifier) modification is emerging as an important post-translational control in transcription. In general, SUMO modification is associated with transcriptional repression. Although many SUMO-modified transcription factors and co-activators have been identified, little is known about the mechanism underlying SUMOylation-elicited transcriptional repression. Here, we summarize that SUMO modification of transcription factors such as androgen receptor, glucocorticoid receptor, Smad4 and CBP [CREB (cAMP-response-element-binding protein)-binding protein] co-activator results in the recruitment of a transcriptional co-repressor Daxx, thereby causing transcriptional repression. Such a SUMO-dependent recruitment of Daxx is mediated by the interaction between the SUMO moiety of SUMOylated factors and Daxx SUMO-interacting motif. Interestingly, the transrepression effect of Daxx on these SUMOylated transcription factors can be relieved by SUMOylated PML (promyelocytic leukaemia) via altering Daxx partition from the targeted gene promoter to PML nuclear bodies. Because Daxx SUMO-interacting motif is a common binding site for SUMOylated factors, a model of competition for Daxx recruitment between SUMOylated PML and SUMOylated transcription factors was proposed. Together, our findings strongly suggest that Daxx functions as a SUMO reader in the SUMO-dependent regulation of transcription and subnuclear compartmentalization.
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PMID:Daxx mediates SUMO-dependent transcriptional control and subnuclear compartmentalization. 1803 Dec 30


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