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)

Despite the understanding of the importance of phosphoinositide 3-kinase (PI 3-K) signaling pathway in the regulation of cellular proliferation, little is known about its role during phorbol 12-myristate 13-acetate (PMA)-induced differentiation in human leukemia cells. Here, we report a novel finding that PI 3-K inhibition by LY294002 significantly increases p21WAF1/Cip1 expression in PMA-stimulated human leukemia cells NB4 and THP1. LY294002 potentiated expression of p21WAF1/Cip1 via a p53-independent mechanism and did not affect mitogen activated protein kinase (MAPK) activation. Electrophoretic mobility shift (EMSA) experiments revealed that blocking of PI 3-K was associated with increased binding of transcription factor Sp1 to the PMA-responsive sites on the p21WAF1/Cip1 promoter. Pretreatment with rapamycin, an inhibitor of mTOR kinase, decreased the expression of p21WAF1/Cip1 protein in PMA-stimulated NB4 cells. The level of PMA-induced p21WAF1/Cip1 protein expression was lower in NB4 cells overexpressing wild type protein kinase C zeta (PKC zeta) compared to those transfected with empty vector or with kinase inactive PKC zeta. Sp1 binding to the p21WAF1/Cip1 promoter was completely lost in a wild type PKC zeta overexpressing and PMA-stimulated NB4 cells. We demonstrate that PI 3-K signaling pathway suppresses PMA-induced expression of p21WAF1/Cip1 in human leukemia cells, and that this effect is partly mediated by PKC zeta.
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PMID:PI 3-K signaling pathway suppresses PMA-induced expression of p21WAF1/Cip1 in human leukemia cells. 1728 1

Originally identified as an essential component of the herpes simplex virus immediate early (IE) gene enhancer complex, the transcriptional coactivator host cell factor-1 (HCF-1) has been implicated in a broad range of cellular regulatory circuits. The protein mediates activation through multiple interactions with transcriptional activators, coactivators, and chromatin remodeling complexes. However, the mechanisms involved in HCF-1-dependent transcriptional stimulation were undefined. By using a minimal HCF-1-dependent promoter and a model activator, the varicella zoster IE62 protein, it was determined that HCF-1 was not required for the assembly of the RNAPII basal complex, which depended solely on IE62 in conjunction with the cellular factor Sp1. In contrast, HCF-1 was required for recruitment of the histone methyltransferases Set1 and MLL1 (mixed-lineage leukemia 1), leading to histone H3K4 trimethylation and transcriptional activation. Similarly, in a varicella zoster virus lytic infection, HCF-1, Set1, and MLL1 were recruited to the viral genomic IE promoter, suggesting an essential role for HCF-1 in chromatin modification and remodeling during initiation of lytic infection. The results indicate that one biological rationale for the incorporation of the viral IE activators in the viral particle is to recruit HCF-1/histone methyltransferase complexes and promote assembly of the viral IE gene promoters into transcriptionally active chromatin. These studies also contribute to the model whereby the induced nuclear transport of HCF-1 in sensory neurons may be critical to the reactivation of latent herpesviruses by promoting the activation of chromatin modifications.
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PMID:The coactivator host cell factor-1 mediates Set1 and MLL1 H3K4 trimethylation at herpesvirus immediate early promoters for initiation of infection. 1757 10

Low expression of ID4 gene is tightly related with carcinogenesis and high expression shows a definite anti-leukemia effect, though little expression in some leukemia cells. The main purpose of this preliminary work was to analyze the construction of ID4 gene promoter and to predict the cis elements in the ID4 promoter region by scanning the drug candidate with bioinformatics method. All these work are the primary part for finding effective drugs in the treatment of leukemia via the way of ID4 expression regulation. According to the data in GenBank and Internet platform, the 5'-untranslated sequence just upstream of ID4 ORF was virtually cloned. TESS, Genomatix and GenBank databank were used to analyze the cis elements in this area. RSA was used to find the distribution patterns for all these possible elements. SAGE and GEO datasets were used to find active substances which have the effect on the ID4 expression. The rsults indicated that ID4 had a type II promoter with a typical TATA box-45 bp upstream the transcriptional original site. There were a lot of various cis elements in the 5'-untranslated region upstream, including both positive element candidates such as Sp1, c-Myb, abaA, GR, ER, Zeste and C/EBPalpha and negative element candidates such as CCAAT-binding factor, GCF, WT1-KTS, HiNF-C and EGR2. It is concluded that estrogen, dexamethasone, thyroid hormone and follicle stimulating hormone may participate in the regulation of ID4 gene expression in both positive and negative manners.
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PMID:[Bioinformatics scan analysis for predicting drug targeted modulation on ID4 gene expression]. 1760 73

Platycodin D (PD) is a major constituent of triterpene saponins found in the root of Platycodon grandiflorum. Recent studies have demonstrated that PD is a potentially interesting candidate for use in cancer chemotherapy. However, the molecular mechanisms responsible for PD-induced telomerase inhibition remain to be poorly known. In this study, we examined the effects of PD treatment on telomerase activity in different human leukemia cell lines. At concentrations between 10 and 20 microM, PD exerted a dose-dependent direct cytotoxic effect and inhibition of telomerase activity via downregulation of hTERT expression. Because c-Myc and Sp1 are known to directly regulate transcription of hTERT, we also evaluated the expression and DNA binding activity of these proteins. PD treatment reduced c-Myc and Sp1 protein levels and DNA binding activities in a dose-dependent manner. We also observed that PD treatment downregulates the activation of Akt, thereby reducing the phosphorylation and nuclear translocation of hTERT. We conclude that PD has direct cytotoxic effect on human leukemia cells and suppresses telomerase activity through transcriptional and posttranslational suppression of hTERT.
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PMID:Platycodin D induces apoptosis and decreases telomerase activity in human leukemia cells. 1809 27

Recent studies indicate that gossypol possesses potent antitumor activities in vitro and in vivo. The nuclear factor-kappa B (NF-kappaB) plays an important role in tumor cell growth, proliferation, invasion, and survival. In this study, we investigated the effects and the molecular mechanisms of gossypol on NF-kappaB activation and NF-kappaB-related gene expression in human leukemia U937 cells. Treatment with concentrations of gossypol greater than 10 microM resulted in significant cell cytotoxicity and DNA fragmentation, indicative of apoptosis. Treatment with 10 microM gossypol also induced caspase-3 activation and poly(ADP-ribose)polymerase (PARP) cleavage, and resulted in the induction of apoptosis in approximately 20% of cells as determined by annexin-V staining 24h after treatment. Furthermore, gossypol exposure decreased the DNA-binding activity of NF-kappaB in a concentration-dependent manner. Treatment with gossypol also downregulated expression of NF-kappaB-regulated gene products, including inhibitor of apoptosis protein (IAP)-1, IAP-2, and X-linked IAP. Attenuation of NF-kappaB activity by pretreatment with PDTC, an NF-kappaB nuclear translocation inhibitor, significantly induced apoptosis in the presence of gossypol. Gossypol also suppressed NF-kappaB p65 mRNA accumulation, resulting in suppression of total NF-kappaB activity. This was associated with a downregulation of Sp1-binding activity, a transcription factor controlling p65 transcription. These results suggest that gossypol-induced apoptosis partially involves suppression of NF-kappaB activity.
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PMID:Gossypol suppresses NF-kappaB activity and NF-kappaB-related gene expression in human leukemia U937 cells. 1831 60

TG-interacting factor (TGIF) is a homeobox transcriptional repressor that has been implicated in holoprosencephaly and various types of cancer, including leukemias. In this study, we provide the first detailed description of the TGIF locus characterizing 12 TGIF splice isoforms. These isoforms have similar open reading frames but different 5' untranslated regions. TGIF expression data are presented from multiple tissues, cell lines and primary leukemia cells. Isoform-specific real-time PCR analysis showed that even though these isoforms were broadly expressed all except isoform 4, had very low level of expression. In fact, isoform 4 was the predominant TGIF isoform expressed in all tissues analyzed. Since TGIF, levels have recently implicated to play a role in acute myelogenous leukemia we proceeded to characterize the minimal promoter region of isoform 4 as a first step in understanding mechanisms of TGIF expression. As expected for homeobox genes, the minimal promoter region for isoform 4 has multiple Sp1 binding sites and a CpG island raising the possibility that the low TGIF expression seen in some AML patients and leukemia cell lines may be secondary to methylation. Further characterization of expression from this promoter using 5-Aza-2'-deoxycytidine treatment and transient expression assays showed that decreased TGIF expression is likely secondary to active repression and not because of promoter methylation. A detailed characterization of this complex locus is important as it may help to clarify the functions of this gene in brain development and leukemia biology.
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PMID:Genomic structure, alternative splicing and expression of TG-interacting factor, in human myeloid leukemia blasts and cell lines. 1845 19

The persistence of human T-cell leukemia/lymphoma virus-I (HTLV-I)-infected cells is dependent upon clonal expansion and up-regulation of telomerase (hTERT). We have previously found that in interleukin (IL)-2-independent transformed HTLV-I cells, Tax strongly activates the hTERT promoter through nuclear factor-kappaB (NF-kappaB)-mediated Sp1 and c-Myc activation. In IL-2-dependent cells and adult T-cell leukemia/lymphoma (ATLL) patient samples, however, Tax expression is very low to undetectable, yet these cells retain strong telomerase activity. This suggests the existence of compensatory mechanisms in IL-2-dependent cells and ATLL patients. In this study, we demonstrate that telomerase activity is significantly decreased upon IL-2 withdrawal in immortalized HTLV-I cell lines. Inhibition of PI3K or AKT signaling pathways reduced telomerase activity in HTLV-I cells. We found that IL-2/IL-2R signaling was associated with a PI3K-dependent/AKT-independent transcriptional up-regulation of the endogenous hTERT promoter. We found that activation of the PI3K pathway mediated cytoplasmic retention of the Wilms tumor (WTI) protein, which strongly suppressed the hTERT promoter. The importance of this regulatory pathway for telomerase expression is underscored by findings that the PI3K pathway is commonly found activated in cancer cells.
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PMID:Central role of PI3K in transcriptional activation of hTERT in HTLV-I-infected cells. 1880 72

p53-upregulated modulator of apoptosis (PUMA) plays an essential role in p53-dependent apoptosis following DNA damage. PUMA also mediates apoptosis independent of p53. In this study, we investigated the role and mechanism of PUMA induction in response to serum starvation in p53-deficient cancer cells. Following serum starvation, the binding of Sp1 to the PUMA promoter significantly increased, whereas inhibition of Sp1 completely abrogated PUMA induction. p73 was found to be upregulated by serum starvation and mediate PUMA induction through the p53-binding sites in the PUMA promoter. Sp1 and p73beta appeared to cooperatively activate PUMA transcription, which is inhibited by the phosphoinsitide 3-kinase (PI3K)-protein kinase B (AKT) pathway. Furthermore, knockdown of PUMA suppressed serum starvation-induced apoptosis in leukemia cells. Our results suggest that transcription factors Sp1 and p73 mediate p53-independent induction of PUMA following serum starvation to trigger apoptosis in human cancer cells.
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PMID:Sp1 and p73 activate PUMA following serum starvation. 1857 60

The human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) gene is encoded by the minus strand of the HTLV-1 provirus and transcribed from the 3' long terminal repeat (LTR). HBZ gene expression not only inhibits the Tax-mediated activation of viral gene transcription through the 5' LTR but also promotes the proliferation of infected cells. However, the HBZ promoter region and the transcriptional regulation of the gene have not been studied. In this study, we characterize the promoters of the spliced version of the HBZ gene (sHBZ) and the unspliced version of the HBZ gene (usHBZ) by luciferase assay. Both promoters were TATA-less and contained initiators and downstream promoter elements. Detailed studies of the promoter for the sHBZ gene showed that Sp1 sites were critical for its activity. The activities of the sHBZ and usHBZ gene promoters were upregulated by Tax through Tax-responsible elements in the 3' LTR. We compared the functions of the proteins derived from the sHBZ and usHBZ transcripts. sHBZ showed a stronger suppression of Tax-mediated transcriptional activation through the 5' LTR than did usHBZ; the level of suppression correlated with the level of protein produced. The expression of sHBZ had a growth-promoting function in a T-cell line, while usHBZ expression did not. This study demonstrates that Sp1 is critical for sHBZ transcription, which accounts for the constitutive expression of the sHBZ gene. Functional differences between sHBZ and usHBZ suggest that the sHBZ gene plays a significant role in the proliferation of infected cells.
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PMID:Transcriptional control of spliced and unspliced human T-cell leukemia virus type 1 bZIP factor (HBZ) gene. 1865 54

In this study, we found that pectenotoxin-2 (PTX-2) decreased cell viability and inhibited telomerase activity with downregulation of hTERT expression in human leukemia cells. PTX-2 treatment also reduced c-Myc and Sp1 gene expression and DNA binding activity. Further chromatin immunoprecipitation assay demonstrated that PTX-2 attenuated the binding of c-Myc and Sp1 to the regulatory regions of hTERT. We also observed that PTX-2 treatment attenuated the phosphorylation of Akt, thereby reducing the phosphorylation and nuclear translocation of hTERT. We concluded that PTX-2 suppressed telomerase activity through the transcriptional and post-translational suppression of hTERT and this process precedes cellular differentiation of human leukemia cells.
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PMID:Pectenotoxin-2 represses telomerase activity in human leukemia cells through suppression of hTERT gene expression and Akt-dependent hTERT phosphorylation. 1877 1


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