The human T-cell leukemia virus type 1 (HTLV-1)-encoded Tax protein activates viral transcription through interaction with the cellular transcription factor CREB (cyclic AMP response element [CRE] binding protein).Although Tax stabilizes the binding of CREB to the Tax-responsive viral CREs in the HTLV-1 promoter, the precise molecular mechanism by which Tax mediates strong transcriptional activation through CREB remains unclear. In this report, we show that Tax Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus responsible for an aggressive and fatal malignancy called adult T-cell leukemia (for a review, see reference 16). The viral genome encodes a unique oncoprotein, called Tax, which is a key regulatory protein that appears to facilitate the transition from viral latency to high levels of virion production in the infected T cell. Tax mediates the emergence from latency via strong transcriptional activation of the HTLV-1 genome. The precise molecular mechanism by which Tax activates viral transcription has been widely studied but is not fully understood. Tax does not bind DNA directly (3,8,19,32) but interacts with host cell proteins to stimulate viral transcription through three 21-bp repeat sequences in the transcriptional control region of the virus (10,17,23,31,36,38,39). The three 21-bp repeats each contain an off-consensus core octanucleotide sequence with similarity to the cyclic AMP (cAMP) response element (CRE). A short run of GC-rich nucleotides immediately flanks the core CRE sequences within each of the 21-bp repeats. Together, the CRE and GC-rich flanks form a critical DNA element (called the viral CRE) that is obligatory for Tax transactivation in vivo (11,18,23,29,30). These viral CREs have been shown to serve as binding sites for several members of the basic leucine zipper (bZIP) family of cellular transcription factors. Specifically, the CRE binding protein (CREB) appears to have the most prominent role in mediating Tax transcriptional activation through the viral CREs in the HTLV-1 promoter (1,2,9,11,15,27,(45)(46)(47)(48)(49). Recent studies have shown that in the absence of Tax, the interaction between CREB and the viral CRE is highly unstable, resulting in rapid dissociation of CREB from the viral promoter. In the presence of Tax, the dissociation rate of CREB from the viral CRE is decreased and the equilibrium binding affinity is increased (7,11,44,45). Several lines of evidence indicate that Tax interacts primarily, although not exclusively, with the bZIP region of CREB to stabilize CREB binding to the weak viral CRE sequences (2,7,11,15,46). This binding stabilization by Tax appears to be accomplished through both an increase in CREB dimerization and stabilization of the helical structure of CREB's bZIP domain (7,37,42). Together, these studies support a model in which Tax transactivates HTLV-1 gene expression by increasing the number of CREB molecules bound to the viral promoter, leading to transcriptional activation of the virus and enhanced virion production. Unfort...
Objectives: Diagnosing acute appendicitis is a daunting clinical challenge, as there is no single test that reliably distinguishes acute appendicitis from other etiologies of acute abdominal pain. In this study, the authors examined whether circulating levels of S100A8 ⁄ A9 could be useful as a marker to aid in the diagnosis of acute appendicitis.Methods: Plasma samples from emergency department (ED) patients with acute abdominal pain (n = 181) were tested using an immunoassay for S100A8 ⁄ A9.Results: The sensitivity and specificity for S100A8 ⁄ A9 in diagnosing acute appendicitis were estimated to be 93% (95% confidence interval [CI] = 81% to 97%) and 54% (95% CI = 45% to 62%), respectively. Negative predictive value (NPV) was 96% (95% CI = 89% to 99%), and positive predictive value (PPV) was 37% (95% CI = 28% to 47%). Performance characteristics of elevated white blood cell (WBC) count were also estimated: sensitivity 63% (95% CI = 47% to 76%), specificity 67% (95% CI = 59% to 75%), NPV 86% (95% CI = 78% to 91%), and PPV 36% (95% CI = 26% to 47%).Conclusions: This is the first report exploring the relationship between circulating S100A8 ⁄ A9 and acute appendicitis and establishes proof of concept for this biomarker as a diagnostic test for acute appendicitis. Further studies are indicated to optimize the use of this biomarker, in conjunction with other established approaches.ACADEMIC EMERGENCY MEDICINE 2010; 17:333-336 ª
Herpes simplex virus type 1 (HSV-1) establishes a latent infection in neurons of the peripheral nervous system. During latent HSV-1 infection, viral gene expression is limited to latency-associated transcripts (LAT).HSV-1 remains latent until an unknown mechanism induces reactivation. The ability of the latent virus to periodically reactivate and be shed is essential to the transmission of disease. In vivo, the stimuli that induce reactivation of latent HSV-1 include stress, fever, and UV damage to the skin at the site of initial infection. In vitro, in primary neurons harboring latent HSV-1, nerve growth factor (NGF) deprivation or forskolin treatment induces reactivation. However, the mechanism involved in the induction of reactivation remains poorly understood. During latent herpes simplex virus type 1 (HSV-1) infection in sensory neurons, the viral genome is maintained in a nonreplicating state and viral gene expression is silenced, with the exception of the viral gene that encodes the latency-associated transcripts (LAT) (34). Reactivation of latent HSV-1 is induced by many different stimuli, including fever, stress, and UV irradiation or abrasion to the skin. Studies using LAT mutants indicate that LAT enhances the establishment of latency as well as the reactivation of latent 6,11,22,23,33). The signaling mechanisms controlling the induction of reactivation of latent HSV-1 are not yet understood.Cyclic AMP (cAMP) and nerve growth factor (NGF)-mediated pathways are involved in the induction of reactivation. Forskolin, chlorophenylthio-cAMP, or NGF deprivation results in reactivation of latent HSV-1 in primary neuronal cultures (29). Activation of these pathways is shown to result in phosphorylation and activation of the CRE-binding protein (CREB) (8, 9). Functional CREB response elements (CREs) have been identified within the LAT promoter at positions Ϫ85 and Ϫ43 from the site of transcription initiation (4,15,24). The CRE at Ϫ43 has been shown to be cAMP responsive in transient-transfection assays, and mutagenesis of this CRE results in reduced reactivation in rabbits latently infected with the recombinant virus (4). Characterization of the CRE at Ϫ85 is primarily limited to the observation that members of the CREB/ATF family can interact with the promoter in electrophoretic mobility shift assays (13, 17). Based on this evidence, it is possible that CREs in the LAT promoter may have a role in signaling that results in the reactivation of latent HSV-1.Previous studies have focused on activation of LAT transcription by signaling pathways (15,24). Based on the presence of elements in the promoter of LAT, the role of the inducible cAMP early repressors (ICER) in the induction of reactivation of latent HSV-1 was examined. The CRE modulator (CREM) gene family encodes transcriptional activators and repressors that are structurally related to the CREB/ATF family (26). The best-characterized CREM repressors are the ICER isoforms (18). ICER is a member of the basic-leucine zipper family and represses by virtue of i...
Tax, the transforming protein of human T-cell leukemia virus type 1 (HTLV-1), is required for strong activation of HTLV-1 transcription. This activation is mediated through interaction with the KIX domain of the cellular coactivator CREB binding protein (CBP). In this study we examined the possibility that the Tax-KIX interaction may mediate effects on cellular gene transcription in vivo, as a growing number of cellular transcription factors have been shown to utilize CBP as a coactivator. We tested the ability of Tax to deregulate the activity of the cellular transcription factor, c-Myb, since both Tax and c-Myb interact with the KIX domain of CBP. Our results show that in vivo, Tax antagonizes the transcriptional activity of c-Myb and, reciprocally, c-Myb antagonizes the transcriptional activity of Tax. Furthermore, c-Myb competes for KIX binding to Tax in vitro, indicating that these two transcription factors bind CBP in a mutually exclusive manner. This novel mechanism of transcriptional interference by Tax may promote globally deregulated cellular gene expression in the HTLV-1-infected cell, possibly leading to leukemogenesis.
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