Activation of Tax protein by c-Jun-N-terminal kinase is not dependent on the presence or absence of the early growth response-1 gene product (original) (raw)
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Oncology Reports, 2012
Retinoids, including vitamin A (retinol) and its analogues, are critical for a variety of biological functions. In this study, we report that all-trans retinoic acid (ATRA) decreases Jun N-terminal kinase 1 (JNK-1) activity, antagonizing the effect of the Tax protein in Jurkat leukemia T cells transiently transfected for expressing the Tax protein. The Tax protein is one of the products of the human T-cell leukemia virus type 1 (HTLV-1) which is the etiologic agent of adult T-cell leukemia (ATL), an aggressive neoplasia of CD4 + T cells. The decrease in JNK-1 activity was followed by a marked decrease in the expression of interleukin (IL)-2 and a weak increase in interferon (IFN)-γ in Jurkat cells treated with ATRA in a dose-dependent manner, suggesting a correlation between the expression of JNK-1 and the activity of the Tax protein. However, the expression levels of IL-4 and IL-10 were enhanced in cells transfected with Tax, compared with the levels in untransfected cells, but the expression levels were not affected following ATRA treatment. In transfection studies using a luciferase reporter construct expressing the IL-2 promoter or a tandem repeat of AP-1 or NF-κB, the inhibitory effect of ATRA on the IL-2 promoter and AP-1 construct was confirmed at the transcriptional level. However, the inhibitory effect in the NF-κB reporter construct was only marginal. In addition, our data demonstrated that JNK-1 is constitutively activated in Jurkat leukemia T cells expressing the Tax protein, suggesting that JNK-1 is required for Tax-induced proliferation of Jurkat leukemia cells.
PLOS ONE, 2016
Tax1 encoded by the human T-cell leukemia virus type 1 (HTLV-1) has been believed to dysregulate the expression of cellular genes involved in cell survival and mortality, leading to the development of adult T-cell leukemia (ATL). The function of Tax1 in ATL development however is still controversial, primarily because Tax1 induces cell cycle progression and apoptosis. To systemically understand cell growth phase-dependent induction of cell survival or cell death by Tax1, we established a single experimental system using an interleukin 2 (IL-2)-dependent human T-cell line Kit 225 that can be forced into resting phase by IL-2 deprivation. Introduction of Tax1 and HTLV-2 Tax (Tax2B) decreased mitochondrial activity alongside apoptosis in growing cells but not in resting cells. Cell cycle profile analysis indicated that Tax1 and Tax2B were likely to perturb the S phase in growing cells. Studies with Tax1 mutants and siRNA for NF-κB/RelA revealed that Tax1-mediated cell growth inhibition and apoptosis in growing Kit 225 cells depend on RelA. Interestingly, inactivation of the non-canonical NF-κB and p38 MAPK pathways relieved Tax1-mediated apoptosis, suggesting that the Tax1-NF-κB-p38 MAPK axis may be associated with apoptosis in growing cells. Inflammatory mediators such as CCL3 and CCL4, which are involved in oncogeneinduced senescence (OIS), were induced by Tax1 and Tax2B in growing cells. In contrast, RelA silencing in resting cells reduced mitochondrial activity, indicating that NF-κB/RelA is also critical for Tax1-mediated cell survival. These findings suggest that Tax1-mediated cell survival and death depend on the cell growth phase. Both effects of Tax1 may be implicated in the long latency of HTLV-1 infection.
Positive regulation of jun/AP-1 by E1A
Molecular and cellular biology, 1991
Proteins encoded by the adenovirus E1A oncogene are capable of positive and negative transcriptional regulation of both viral and cellular genes. E1A regulatory function is commonly thought to involve modifications of specific cellular factors that interact with responsive promoters. In this report we present evidence that E1A induces the activity of the jun/AP-1 transcription factor in three different cell types: P19, JEG-3, and HeLa. AP-1 binds to 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive elements (TREs); therefore, E1A might modulate a specific signal transduction pathway normally induced by activation of the protein kinase C. Binding of jun/AP-1 to a TRE is induced in all cell types studied when E1A is expressed. We observe that the expression of endogenous c-jun and jun B genes is induced by E1A, which directly transactivates the promoters of c-fos, c-jun, and jun B. Similar inducibility is obtained by treatment with retinoic acid and differentiation of P19-embryona...
Cancer research, 1998
The transactivator protein, Tax, from the human T-cell leukemia virus type I (HTLV-I) transactivates both viral and cellular genes. Previously, we had shown that interleukin 8 (II.-8) is constitutively expressed in HTLV-I-infected cells and in cells transiently expressing Tax. We show here that the II-X promoter is Tax responsive in Jurkat T cells. Further more, using several deletion and mutated plasmids of the 5'-flanking regulatory region of the ll.-fi gene linked to the luciferase gene as a reporter and mutant tax gene expression vectors, we have established that both AP-1 at-126 to-120 and nuclear factor (NF)-KB-like rô-element at-80 to â€"¿ 71 are essential and sufficient for the induction of the IL-8 gene by HTLV-I Tax. In addition, overexpression of the dominant-negative mutants of NF-KB inhibitor molecules, In-Hir and Ik-H/i, abolished the Tax-induced activation of IL-8 gene. Gel mobility shift assays detected proteins specifically binding to the AP-1 and NF-KB-like sites in Taxexpressing T-cell lines infected with HTLV-I. Similarly, the nuclear translocation of proteins specifically bound to these two motifs was shown in JPX-9 cells, a subclone of Jurkat cells, carrying the Tax sequences under the control of an inducible promoter. Taken together, these results suggest that the cooperation of transcription factors NF-KB and AP-1 is essential for transactivation of IL-8 gene by HTLV-I Tax.
Molecular and cellular biology, 1998
Tax corresponds to a 40-kDa transforming protein from the pathogenic retrovirus human T-cell leukemia virus type 1 (HTLV-1) that activates nuclear expression of the NF-kappaB/Rel family of transcription factors by an unknown mechanism. Tax expression promotes N-terminal phosphorylation and degradation of IkappaB alpha, a principal cytoplasmic inhibitor of NF-kappaB. Our studies now demonstrate that HTLV-1 Tax activates the recently identified cellular kinases IkappaB kinase alpha (IKKalpha) and IKKbeta, which normally phosphorylate IkappaB alpha on both of its N-terminal regulatory serines in response to tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) stimulation. In contrast, a mutant of Tax termed M22, which does not induce NF-kappaB, fails to activate either IKKalpha or IKKbeta. Furthermore, endogenous IKK enzymatic activity was significantly elevated in HTLV-1-infected and Tax-expressing T-cell lines. Transfection of kinase-deficient mutants of IKKalpha and IKKb...
Journal of virology, 1999
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia. Tax, the viral protein, is thought to be crucial in the development of the disease, since it transforms healthy T cells in vitro and induces tumors in transgenic animals. We examined the effect of Tax activity on the growth of the interleukin-2 (IL-2)-dependent T-cell line CTLL-2. Stable expression of Tax in CTLL-2 transformed cell growth from being IL-2 dependent to IL-2 independent. Tax stimulated transcription through NF-kappaB and the cyclic AMP-responsive element-like sequence in the HTLV-1 promoter. The finding of Tax mutants segregating these two pathways suggested that the NF-kappaB pathway was essential for IL-2-independent growth of CTLL-2 cells while the CRE pathway was unnecessary. However, both pathways were necessary for another transformation-related activity (colony formation in soft agar) of CTLL-2/Tax. Our results show that Tax has at least two distinct activities on T cell...