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 Tax protein encoded by the human T-cell leukemia virus type 1 (HTLV-1) activates viral gene expression via the ATF/CREB pathway. Tax also induces a variety of cellular genes through activation of the transcription factor NF-kappaB. The ability of Tax to activate the NF-kappaB pathway plays an essential role in HTLV-1-induced cellular transformation. This review briefly summarizes the remarkable discoveries of the past several years that have greatly advanced our knowledge on signal-mediated activation of the NF-kappaB pathway. It highlights our current understanding of how viral agents like Tax modulate cellular signaling machinery to activate the NF-kappaB pathway.
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PMID:Regulation of NF-kappaB by the HTLV-1 Tax protein. 1044 Feb 24

The human T-cell leukemia virus type-1 (HTLV-I)-encoded Tax protein enhances viral gene transcription through interaction with three repeated DNA elements located in the viral promoter. These elements, called viral CREs, are composed of an off-consensus eight base-pair cyclic AMP response element (CRE), immediately flanked by sequences that are rich in guanine and cytosine residues. Recent biochemical experiments have demonstrated that in the presence of the cellular protein CREB, Tax directly binds the viral CRE G+C-rich sequences via interaction with the minor groove. To determine the functional significance of the Tax-DNA interaction, we synthesized minor groove-binding pyrrole-imidazole polyamides which bind specifically to the G+C-rich sequences in the viral CREs. At concentrations where the polyamides specifically protect the G+C-rich sequences from MPE:Fe cleavage, the polyamides block the Tax-DNA interaction. At precisely these same concentrations, the polyamides specifically inhibit Tax transactivation in vitro, without altering CREB-activated transcription or basal transcription from the same promoter. Together, these data provide strong evidence that Tax-viral CRE interaction is essential for Tax function in vitro, and suggest that targeted disruption of the Tax-DNA minor groove interaction with polyamides may provide a novel approach for inhibiting viral replication in vivo.
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PMID:The tax protein-DNA interaction is essential for HTLV-I transactivation in vitro. 1045 85

Tumour necrosis factor alpha (TNF-alpha) inflammatory activity is mediated, at least in part, by prostaglandin E(2)(PGE(2)). In osteoarthritis (OA), other cytokines are believed to play a role by interacting with TNF-alpha. Using OA synovial fibroblasts, we investigated the effects of interleukin 8 (IL-8), leukaemia inhibitory factor (LIF) and IL-11 on the level of TNF-alpha-induced PGE(2), and their impact on the TNF-alpha-induced cellular signalling cascades including the TNF-receptor (TNF-R), soluble TNF-R (TNF-sR), cytoplasmic phospholipase A2 (cPLA2), cyclooxygenase 2 (COX-2), and the transcription factors NF-kappaB, C/EBP, CREB and AP-1.IL-8 increased in a synergistic manner (282% at 5 ng/ml) and LIF in an additive fashion (69% at 50 ng/ml) the TNF-alpha-induced PGE(2)release, while IL-11 reduced it (52% at 5 ng/ml). IL-8 (5 ng/ml) and LIF (50 ng/ml) alone upregulated (30%) the TNF-R binding level, but significantly downregulated the TNF-alpha-induced levels (P<0.007 and P<0.004, respectively) and the TNF-sR55 level. In contrast, IL-11 reduced the basal level by 18% (P<0.005) and the TNF-alpha-induced level of TNF-R by 51% (P<0.01) as well as decreasing both TNF-sR55 and TNF-sR75. The COX-2 synthesis level was increased by IL-8 and LIF under TNF-alpha treatment but downregulated by IL-11. IL-8 and LIF either alone or under TNF-alpha treatment increased the cPLA2 synthesis, while IL-11 decreased the level under both conditions. Interestingly, IL-8 induced in a synergistic manner and LIF in an additive fashion, the level of cPLA2 activity. IL-8 and LIF had no effect on the TNF-alpha-induced NF-kappaB accumulation, while IL-11 significantly decreased it (P<0. 02). All three cytokines inhibited TNF-alpha-induced C/EBP, but no true effect was noted for AP-1 and CREB in the presence of TNF-alpha. These results indicate that IL-8 synergizes and LIF potentiates the TNF-alpha PGE(2)effect which appears to be mediated mostly by increasing cPLA2 activity level. On the other hand, IL-11 alone had no effect on the PGE(2)release, but in conjunction with TNF-alpha, this cytokine showed anti-inflammatory properties. This study provides a rational foundation to develop therapeutic strategies for the treatment of OA by shedding light on the mechanisms of action of three prominent cytokines at work in articular joint tissues.
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PMID:Differential effects of IL-8, LIF (pro-inflammatory) and IL-11 (anti-inflammatory) on TNF-alpha-induced PGE(2)release and on signalling pathways in human OA synovial fibroblasts. 1062 27

Over the past decade, the involvement of tyrosine kinases in signal transduction pathways evoked by cytokines has been intensively investigated. Only relatively recently have the roles of serine/threonine kinases in cytokine-induced signal transduction and anti-apoptotic pathways been examined. Cytokine receptors without intrinsic kinase activity such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and the interferons were thought to transmit their regulatory signals primarily by the receptor-associated Jak family of tyrosine kinases. This family of tyrosine kinases activates STAT transcription factors, which subsequently transduced their signals into the nucleus to modulate gene expression. Cytokine receptors with intrinsic tyrosine kinase activity such as c-Kit were initially thought to transduce their signals independently of serine/threonine kinase cascades. Recently, both of these types of receptor signaling pathways have been shown to interact with serine/threonine kinase pathways as maximal activation of these tyrosine kinase regulated cascades involve serine/threonine phosphorylation modulated by, for example MAP kinases. A common intermediate pathway initiating from cytokine receptors is the Ras/Raf/MEK/ERK (MAPK) cascade, which can result in the phosphorylation and activation of additional downstream kinases and transcription factors such as p90Rsk, CREB, Elk and Egr-1. Serine/threonine phosphorylation is also involved in the regulation of the apoptosis-controlling Bcl-2 protein, as certain phosphorylation events induced by cytokines such as IL-3 are anti-apoptotic, whereas other phosphorylation events triggered by chemotherapeutic drugs such as Paclitaxel are associated with cell death. Serine/threonine phosphorylation is implicated in the etiology of certain human cancers as constitutive serine phosphorylation of STATs 1 and 3 is observed in chronic lymphocytic leukemia and can be inhibited by the chemotherapeutic drug fludarabine. Serine/threonine phosphorylation also plays a role in the etiology of immunodeficiencies. Activated STAT5 proteins are detected in reduced levels in lymphocytes recovered from HIV-infected individuals and immunocompromised mice. Serine/threonine phosphorylation may be an important target of certain chemotherapeutic drugs which recognize the activated proteins. This meeting report and mini-review will discuss the interactions of serine/threonine kinases with signal transduction and apoptotic molecules and how some of these pathways can be controlled by chemotherapeutic drugs. Leukemia (2000) 14, 9-21.
Leukemia 2000 Jan
PMID:Serine/threonine phosphorylation in cytokine signal transduction. 1063 71

Human T-cell leukemia virus type 1 (HTLV-1) encodes a transcriptional activator, Tax, whose activity is believed to contribute significantly to cellular transformation. Tax stimulates transcription from the proviral promoter as well as from promoters for a variety of cellular genes. The mechanism through which Tax communicates to the general transcription factors and RNA polymerase II has not been completely determined. We investigated whether Tax could function directly through the general transcription factors and RNA polymerase II or if other intermediary factors or coactivators were required. Our results show that a system consisting of purified recombinant TFIIA, TFIIB, TFIIE, TFIIF, CREB, and Tax, along with highly purified RNA polymerase II, affinity-purified epitope-tagged TFIID, and semipurified TFIIH, supports basal transcription of the HTLV-1 promoter but is not responsive to Tax. Two additional activities were required for Tax to stimulate transcription. We demonstrate that one of these activities is poly(ADP-ribose) polymerase (PARP), a molecule that has been previously identified to be the transcriptional coactivator PC1. PARP functions as a coactivator in our assays at molar concentrations approximately equal to those of the DNA and equal to or less than those of the transcription factors in the assay. We further demonstrate that PARP stimulates Tax-activated transcription in vivo, demonstrating that this biochemical approach has functionally identified a novel target for the retroviral transcriptional activator Tax.
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PMID:Identification of poly(ADP-ribose) polymerase as a transcriptional coactivator of the human T-cell leukemia virus type 1 Tax protein. 1066 46

Human T-cell leukemia virus (HTLV) Tax protein has been implicated in the HTLV oncogenic process, primarily due to its pleiotropic effects on cellular genes involved in growth regulation and cell cycle control. To date, several approaches attempting to correlate Tax activation of the CREB/activating transcription factor (ATF) or NFkappaB/Rel transcriptional activation pathway to cellular transformation have yielded conflicting results. In this study, we use a unique HTLV-2 provirus (HTLV(c-enh)) that replicates by a Tax-independent mechanism to directly assess the role of Tax transactivation in HTLV-mediated T-lymphocyte transformation. A panel of well-characterized tax-2 mutations is utilized to correlate the respective roles of the CREB/ATF or NFkappaB/Rel signaling pathway. Our results demonstrate that viruses expressing tax-2 mutations that selectively abrogate NFkappaB/Rel or CREB/ATF activation display distinct phenotypes but ultimately fail to transform primary human T lymphocytes. One conclusion consistent with our results is that the activation of NFkappaB/Rel provides a critical proliferative signal early in the cellular transformation process, whereas CREB/ATF activation is required to promote the fully transformed state. However, complete understanding will require correlation of Tax domains important in cellular transformation to those Tax domains important in the modulation of gene transcription, cell cycle control, induction of DNA damage, and other undefined activities.
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PMID:Human T-cell leukemia virus type 2 tax mutants that selectively abrogate NFkappaB or CREB/ATF activation fail to transform primary human T cells. 1068 80

We have previously demonstrated that the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein represses the trans-activation function of p53 tumor suppressor protein. Recently, several proteins with sequence homology to p53 have been identified. In this study, we demonstrated that Tax represses the trans-activation functions of p73alpha, p73beta, and p51A, the p53-related proteins, as well as p53. Moreover, a mutant Tax of coactivator CBP-binding site (K88A), which activated NF-kappaB but not CREB pathway, could not repress the p73 nor p51 trans-activation functions, indicating that CBP-binding domain of Tax is essential for the suppression of their functions. Using proteins of Gal4-fused N-terminal region of p73 and p51, we showed that Tax-mediated inactivation of p73 or p51 requires for their N-terminal trans-activation domains. Furthermore, only the putative N-terminal trans-activation domains of them did not have enough transcriptional activities and their adjacent regions are essential for their full trans-activation, suggesting the existence of their second trans-activation subdomains. Thus, HTLV-1 Tax inactivated the p53-related proteins through their N-terminal trans-activation domains.
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PMID:Functional impairment of p73 and p51, the p53-related proteins, by the human T-cell leukemia virus type 1 Tax oncoprotein. 1069 1

Previous studies have shown that human T-cell leukemia virus type 1 (HTLV-1) Tax is a key molecule of synoviocyte activation in HTLV-1 associated arthropathy (HAAP). To clarify the molecular mechanism of HTLV-1 Tax-induced transcriptional activation in synoviocytes from HAAP, we investigated the role of cyclicAMP (cAMP)-regulated enhancer (CRE) binding protein (CREB)-binding protein (CBP), as a target molecule of HTLV-1 Tax. Activation of cyclic AMP (cAMP)/protein kinase-A (PK-A) pathway resulted in a significantly high response of CRE promoter in synoviocytes from patients with HAAP as well as in Tax-transiently transfected synoviocytes from patients with rheumatoid arthritis (RA). Mammalian two-hybrid analysis showed that the recruitment of CBP was responsible for CREB activation. Furthermore, PK-A activation induced CBP-Tax complex in synoviocytes from HAAP and the complex contained CREB. These findings demonstrated that complex formation of CBP and Tax is critical for enhanced CREB activity in synoviocytes from HAAP.
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PMID:CBP: A target molecule of HTLV-1 Tax in synoviocyte activation. 1070 98

The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein repressed the transcriptional activity of wild-type p53 through its N-terminal trans-activation domain. Although Tax did not directly bind to p53, this repression required the activation of CREB pathway by Tax. In contrast to a recent report by Pise-Masison et al. (1998a, b) we found that the phosphorylation of p53 on Ser 15 is not a major cause of the Tax-mediated inactivation of p53. However, Tax with a mutation in the coactivator CBP-binding site (K88A), which activates NF-kappaB but not the CREB pathway, could not repress the p53 trans-activation function. Moreover, Tax inhibited p53 binding to CBP in vitro and inhibited synergistic activation of transcription by CBP and p53. Thus, Tax is likely to compete with p53 in binding with CBP, thereby repressing its trans-activation function.
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PMID:HTLV-1 tax oncoprotein represses the p53-mediated trans-activation function through coactivator CBP sequestration. 1073 8

The transactivator protein Tax of human T-cell leukemia virus type I plays an important role in the development of adult T-cell leukemia probably through modulation of growth regulatory molecules including p16(INK4a). The molecular mechanism of leukemogenesis induced by Tax has yet to be elucidated. We analyzed Tax function in the cell cycle using an interleukin-2 (IL-2)-dependent human T-cell line (Kit 225) that can undergo cell cycle arrest at G(0)/G(1) phase by deprivation of IL-2. Tax activated endogenous E2F activity in IL-2-starved Kit 225 cells, resulting in activation of E2F site-carrying promoters of genes involved in G(1) to S phase transition in a cell type-dependent and p16(INK4a)-independent manner. The ability of Tax mutants to activate E2F coincided with that to activate nuclear factors kappaB and AT, sole expression of which, however, did not activate E2F, suggesting involvement of another pathway in activation of E2F. Introduction of Tax by a recombinant adenovirus induced cell cycle progression to G(2)/M phase in resting Kit 225 cells accompanied by endogenous cyclin D2 gene expression. Similarly, Tax-induced cell cycle progression was seen with peripheral blood lymphocytes prestimulated with phytohemagglutinin. Analyses with Tax mutants did not allow Tax-induced cell cycle progression to be differentiated from Tax-dependent activation of E2F, suggesting that Tax induces cell cycle progression presumably through activation of E2F. Nevertheless, infection with an E2F1-expressing virus, which is sufficient for induction of S phase in serum-starved fibroblasts, was not sufficient for either E2F activation or cell cycle progression in IL-2-starved Kit 225 cells, implying differential regulation of E2F activation and cell cycle progression in T-cells that is activated by Tax.
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PMID:Cell type-specific E2F activation and cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. 1075 22


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