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)

Transcriptional activation of human T-cell leukemia virus type 1 (HTLV-1) requires many cellular proteins and the virally encoded transcription factor Tax. Tax binds the three viral cAMP-response elements (CREs) with ATF/CREB (activating transcription factor/cAMP-response element-binding protein) and recruits the cellular coactivators CBP/p300. HTLV-1 also utilizes other cellular transcription factors that bind to the promoter to regulate transcription. One of these factors, Sp1, has been shown to bind to the viral promoter at two elements; one located within the third viral CRE, and the second located between the second and third viral CREs. The functional significance of Sp1 binding at each of these regions of the viral promoter is not completely understood. We set out to characterize Sp1 binding and to evaluate the functional significance of Sp1, both in the absence and presence of Tax. We found that Sp1 binds preferentially to the element located between the second and third viral CREs, and modestly activates transcription in vitro and in vivo. Sp1 was detected at the integrated HTLV-1 promoter in vivo. Surprisingly, point mutagenesis of the strong Sp1 binding site rendered the HTLV-1 reporter plasmid insensitive to Sp1 activation, and dramatically reduced basal transcription in vivo. These data indicate a role for Sp1 in basal level transcription of HTLV-1.
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PMID:The high-affinity Sp1 binding site in the HTLV-1 promoter contributes to Tax-independent basal expression. 1515 51

In immortal cells, the existence of a mechanism for the maintenance of telomere length is critical. In most cases this is achieved by the reactivation of telomerase, a cellular reverse transcriptase that prevents telomere shortening. Here we report that the telomerase gene (hTERT) promoter is up-regulated during transmission of human T-cell lymphotropic virus type-I (HTLV-I) to primary T cells in vitro and in ex vivo adult T-cell leukemia/lymphoma (ATLL) samples, but not asymptomatic carriers. Although Tax impaired induction of human telomerase reverse transcriptase (hTERT) mRNA in response to mitogenic stimulation, transduction of Tax into primary lymphocytes was sufficient to activate and maintain telomerase expression and telomere length when cultured in the absence of any exogenous stimulation. Transient transfection assays revealed that Tax stimulates the hTERT promoter through the nuclear factor kappaB (NF-kappaB) pathway. Consistently, Tax mutants inactive for NF-kappaB activation could not activate the hTERT or sustain telomere length in transduced primary lymphocytes. Analysis of the hTERT promoter occupancy in vivo using chromatin immunoprecipitation assays suggested that an increased binding of c-Myc and Sp1 is involved in the NF-kappaB-mediated activation of the hTERT promoter. This study establishes the role of Tax in regulation of telomerase expression, which may cooperate with other functions of Tax to promote HTLV-I-associated adult T-cell leukemia.
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PMID:Transcriptional activation of hTERT through the NF-kappaB pathway in HTLV-I-transformed cells. 1522 82

Kruppel-like factor 2 (KLF2) is a member of the KLF family of zinc-finger transcription factors and is involved in maintaining T-cell quiescence, regulating preadipocyte differentiation, endothelial cell function and lung development. We used a tetracycline-inducible system in Jurkat T leukemia cells to study the biological role of KLF2 in cellular growth and differentiation. Our results show that expression of KLF2 inhibits cell growth in autonomously proliferating Jurkat cells. Further, 3H-thymidine uptake assays indicate that KLF2 inhibits DNA synthesis in these cells. Moreover, both activation and inhibitory domains are required for KLF2 to suppress Jurkat cell proliferation. In addition, KLF2 upregulates p21WAF1/CIP1 expression. Additionally, we found that KLF2 upregulates p21WAF1/CIP1 promoter activity in Jurkat, HepG2 and SW480 cells. Our analysis shows that the potential KLF2 responsive elements are located between -124 and -60 of the p21WAF1/CIP1 promoter. The sole CACCC site, a sequence recognized by KLF2, in this region is not the element responsive to KLF2. Finally, we determined that the Sp1-3-binding site is the functional responsive element of KLF2 in the p21WAF1/CIP1 promoter, and we conclude that KLF2 directly regulates p21WAF1/CIP1 expression.
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PMID:KLF2 inhibits Jurkat T leukemia cell growth via upregulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1. 1536 32

The molecular mechanisms of the cellular response to different apoptotic effectors are only partially understood. Herein, the role of transcription factors, Sp1 and NFkappaB in differentiation-related and etoposide-induced apoptosis was examined in a number of human leukemia cell lines (HL-60, NB4, HEL, THP-1, K562). This was investigated with respect to the recruitment of one cell-cycle regulating gene, p21 and one cell death gene, FasL. Using electrophoretic mobility shift assay (EMSA), we consistently observed Sp1 and NFkappaB binding activity to the promoter of either gene during cell differentiation and the decrease associated with apoptosis upon long-term treatment with differentiation inducers in HL-60, NB4 and HEL cells. By contrast, Sp1 and NFkappaB binding capacities were lost in all myeloid cell lines undergoing etoposide-induced fast apoptosis. This effect was eliminated by the broad-spectrum caspase inhibitor, benzyloxycarbonyl-valinyl-alaninyl-aspartyl fluoromethylketone, thus restoring transcription factors' binding activity. However, sustained NFkappaB binding to the FasL promoter was noticed in apoptosis undergoing HEL cells treated by etoposide. Our results suggest that p21 and FasL gene activation is required for myeloid leukemia cell survival or maturation but not for cell death via Sp1 and NFkappaB as regulators of these genes. The findings also support the idea of a common mechanism for cellular responses to different apoptotic effectors in malignant hematopoietic cell lines.
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PMID:p21 (Waf1/Cip1) and FasL gene activation via Sp1 and NFkappaB is required for leukemia cell survival but not for cell death induced by diverse stimuli. 1569 38

Glycoprotein VI (GPVI) is an essential platelet receptor for collagens that is exclusively expressed in the megakaryocytic lineage. Transcription of the human gene GP6 is driven largely by GATA-binding protein 1 (GATA-1), specificity protein 1 (Sp1), and Friend leukemia integration 1 (Fli-1). In this report, we show that GPVI expression during megakaryocytic differentiation is dependent on cytosine-phosphate-guanosine (CpG) demethylation that can be initiated by thrombopoietin (TPO). Sodium bisulfite genomic sequencing established that a CpG-rich island within the GP6 promoter region is fully methylated at 10 CpG sites in GPVI-nonexpressive cell lines, such as UT-7/EPO and C8161, but completely unmethylated in GPVI-expressive cell lines, including UT-7/TPO and CHRF288-11. To further confirm the relationship between CpG demethylation and expression of GPVI in primary cells, we treated human cord blood cells with TPO. The GP6 promoter is highly methylated in cord blood mononuclear cells (progenitors) but not in CD41+-enriched cells obtained after TPO differentiation. Furthermore, when UT-7/EPO-Mpl cells, which stably express human C-myeloproliferative leukemia virus ligand (c-Mpl), were treated with TPO, demethylation of the GP6 promoter was induced. In every case, demethylation of the GP6 promoter correlated with an increase in mRNA level. Thus, megakaryocyte-specific expression of the GP6 gene is regulated, in part, by CpG demethylation, which can be directly initiated by TPO.
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PMID:Thrombopoietin initiates demethylation-based transcription of GP6 during megakaryocyte differentiation. 1570 20

Transcription factors of the Sp family are known to play key roles in the regulation of both constitutive as well as cell type- and differentiation stage-specific gene expression. Binding sites for factors of the Sp family (Sp1 and Sp3) have previously been identified within the U3 region of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeat (LTR). Although previous studies have demonstrated that Sp1 and Sp3 can interact with the Tax-responsive element 1 (TRE-1) repeat III, the sequences required for Sp1/Sp3 binding have not been mapped in detail. Herein, we demonstrate that the GC-rich regions flanking the viral cAMP-responsive element (CRE) within TRE-1 repeat III exhibit substantial affinity for both Sp1 and Sp3. We demonstrate that purified Sp1 competes with purified CREB for binding to TRE-1 repeat III due to the physical proximity of the Sp1/Sp3 and ATF/CREB binding sites, while purified Sp1 forms a multiprotein complex with purified CREB in the presence of Tax as demonstrated by electrophoretic mobility shift (EMS) analyses. Sp1 and Sp3 binding to the U3 region of the HTLV-1 LTR in the presence of Tax in vivo was confirmed by chromatin immunoprecipitation using HTLV-1-infected T cells (SLB-1 and C8166). Overexpression of Sp1 was modestly enhanced, while overexpression of Sp3 inhibited basal and Tax-mediated transactivation of the HTLV-1 LTR in U-937 cells (which express relatively low levels of endogenous Sp1 and Sp3). Furthermore, the modest upregulation of LTR activation caused by overexpression of Sp1 could be blocked by site-directed mutagenesis of the GC-rich Sp1/Sp3 binding sites within TRE-1 repeat III. These results suggest that both Sp1 and Sp3 transcription factor binding to TRE-1 repeat III participate in regulation of HTLV-1 viral gene expression.
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PMID:Regulation of human T-cell leukemia virus type 1 gene expression by Sp1 and Sp3 interaction with TRE-1 repeat III. 1671 16

Histone deacetylase inhibitors have a potent role in the strategy for the treatment of leukemias. BML-210 (N-(2-Aminophenyl)-N' phenyloctanol diamine) is the novel histone deacetylase inhibitor, and its mechanism of action has not been characterized. In this study, we examined the in vitro effects of BML-210 on the human leukemia cell lines (NB4, HL-60, THP-1, and K562). We found that BML-210 inhibits the growth of all cell lines and promotes apoptosis in a dose- and time-dependent manner. BML-210 alone induces HL-60 and K562 cell differentiation (up to 30%) to granulocytes and erythrocytes, respectively, and in combination with differentiation agents - all-trans retinoic acid and hemin, markedly potentates it. Those treatments cause G1 arrest and histone H4 acetylation, affects transcription factor NF-kappaB and Sp1 binding activity to their consensus sequences, the p21 or the FasL promoters, and influences expression of Sp1, NF-kappaB, p21 and FasL. These findings suggest that BML-210 could be a promising antileukemic agent to induce apoptosis and to modulate differentiation through the modulation of histone acetylation and gene expression.
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PMID:The novel histone deacetylase inhibitor BML-210 exerts growth inhibitory, proapoptotic and differentiation stimulating effects on the human leukemia cell lines. 1697 4

The EEN (extra eleven nineteen) gene, located on chromosome 19p13, was cloned as a fusion with MLL from a patient with acute myeloid leukemia (AML) with translocation t(11;19)(q23;p13). In this study, we characterized the genomic structure of the EEN gene, including its 5' regulatory region and transcription start site (TSS). We found that Sp1 could bind to the guanine-cytosine (GC)-stretch of the EEN promoter and was critical for the normal EEN expression, whereas the leukemia-associated fusion protein AML1-ETO could aberrantly transactivate the EEN gene through an AML1 binding site. Of note, overexpressed EEN showed oncogenic properties, such as transforming potential in NIH3T3 cells, stimulating cell proliferation, and increasing the activity of transcriptional factor AP-1. Retroviral transduction of EEN increased self-renewal and proliferation of murine hematopoietic progenitor cells. Moreover, Kasumi-1 and HL60-cell growth was inhibited with down-regulation of EEN by RNAi. These findings demonstrate that EEN might be a common target in 2 major types of AML associated with MLL or AML1 translocations, and overexpression of EEN may play an essential role in leukemogenesis.
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PMID:Aberrant transcriptional regulation of the MLL fusion partner EEN by AML1-ETO and its implication in leukemogenesis. 1699 Jun 10

Calcium homeostasis of the endoplasmic reticulum (ER) is involved in intracellular signaling pathways and is implicated in major cell functions such as cell growth, differentiation, protein synthesis and apoptosis. The accumulation of calcium in the ER is performed by specific sarco/endoplasmic reticulum calcium transport ATPases (SERCA iso-enzymes). The expression of biochemically distinct SERCA isoforms is cell type dependent and developmentally regulated. This review summarizes pertinent data about the modulation of the expression of SERCA enzymes during the differentiation of normal and tumor cells. These data support the implication of SERCA pumps and especially SERCA3 in the differentiation program of cancer and leukemia cells. During the multi-step process of colon carcinogenesis, the decrease of SERCA3 expression seems to be linked to enhanced APC/ss-catenin/TCF4 signaling and deficient Sp1-like factor-dependent transcription.
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PMID:[Expression of SERCA pumps during cell differentiation and tumorigenesis: application to colonic carcinogenesis]. 1712 48

Oncoretrovirus, but not lentivirus, displays a high transcriptional readthrough activity in the 3' long terminal repeat (LTR) (Zaiss et al. J. Virol. 76, 7209-7219, 2002). However, the U3-deleted, self-inactivating (SIN) lentiviral LTR also exhibits high transcriptional readthrough activity. Since the canonical "core" polyadenylation signal (AAUAAA) of the lentivirus is located in the R-U5 region, the above finding suggests that additional RNA termination signals must be present in the U3 region. Insertion of alternative termination signals including panhuman T cell leukemia virus type I polyadenylation signal, a 3' end small intron, and a tertiary tRNA motif into the lentiviral SIN LTR did not restore the transcriptional termination function. Functional dissection of the U3 region revealed that 70-80% of the termination signals reside in the transcriptional control region within 124 nt overlapping NFkappaB, Sp1 and TATA binding sites. Serial deletion analysis of the transcriptional control region indicates that the lentiviral enhancer/promoter elements are essential to the RNA termination function. These results characterize the mechanism of lentiviral transcriptional readthrough, which addresses important fundamental and practical issue of RNA readthrough influencing lentiviral gene function and vector safety.
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PMID:Overlapping enhancer/promoter and transcriptional termination signals in the lentiviral long terminal repeat. 1724 75


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