HTLV-1 activates YAP via NF-κB/p65 to promote oncogenesis.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. HTLV-1 exerts its oncogenic functions by interacting with signaling pathways involved in cell proliferation and transformation. Dysregulation of the Hippo/YAP pathway is associated with multiple cancers, including virus-induced malignancies. In the present study, we observe that expression of YAP, which is the key effector of Hippo signaling, is elevated in ATL cells by the action of the HTLV-1 Tax protein. YAP transcriptional activity is remarkably enhanced in HTLV-1-infected cells and ATL patients. In addition, Tax activates the YAP protein via a mechanism involving the NF-κB/p65 pathway. As a mechanism for this cross talk between the Hippo and NF-κB pathways, we found that p65 abrogates the interaction between YAP and LATS1, leading to suppression of YAP phosphorylation, inhibition of ubiquitination-dependent degradation of YAP, and YAP nuclear accumulation. Finally, knockdown of YAP suppresses the proliferation of ATL cells in vitro and tumor formation in ATL-engrafted mice. Taken together, our results suggest that p65-induced YAP activation is essential for ATL pathogenesis and implicate YAP as a potential therapeutic target for ATL treatment.

3D chromatin remodeling potentiates transcriptional programs driving cell invasion.

The contribution of deregulated chromatin architecture, including topologically associated domains (TADs), to cancer progression remains ambiguous. CCCTC-binding factor (CTCF) is a central regulator of higher-order chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains unclear. We find that under physiological conditions, CTCF organizes subTADs to limit the expression of oncogenic pathways, including phosphatidylinositol 3-kinase (PI3K) and cell adhesion networks. Loss of a single CTCF allele potentiates cell invasion through compromised chromatin insulation and a reorganization of chromatin architecture and histone programming that facilitates de novo promoter-enhancer contacts. However, this change in the higher-order chromatin landscape leads to a vulnerability to inhibitors of mTOR. These data support a model whereby subTAD reorganization drives both modification of histones at de novo enhancer-promoter contacts and transcriptional up-regulation of oncogenic transcriptional networks.

Identification of two key biomarkers CD93 and FGL2 associated with survival of acute myeloid leukaemia by weighted gene co-expression network analysis.

Acute myeloid leukaemia (AML) is a biologically heterogeneous haematological malignancy. This study was performed to identify the potential biomarkers for the prognosis and treatment of AML. We applied weighted gene co-expression network analysis to identify key modules and hub genes related to the prognosis of AML using data from The Cancer Genome Atlas (TCGA). In total, 1581 differentially expressed genes (1096 upregulated and 485 downregulated) were identified between AML patients and healthy controls, with the blue module being the most significant among 14 modules associated with AML morphology. Through functional enrichment analysis, we identified 217 genes in the blue module significantly enriched in 'neutrophil degranulation' and 'neutrophil activation involved in immune response' pathways. The survival analysis revealed six genes (S100A9, S100A8, HK3, CD93, CXCR2 and FGL2) located in the significantly enriched pathway that were notably related to AML survival. We validated the expression of these six genes at gene and single-cell levels and identified methylation loci of each gene, except for S100A8. Finally, in vitro experiments were performed to demonstrate whether the identified hub genes were associated with AML survival. After knockdown of CD93 and FGL2, cell proliferation was significantly reduced in U937 cell line over 5 days. In summary, we identified CD93 and FGL2 as key hub genes related to AML survival, with FGL2 being a novel biomarker for the prognosis and treatment of AML.

The SARS-CoV-2 nucleocapsid protein suppresses innate immunity by remodeling stress granules to atypical foci.

Viruses deploy multiple strategies to suppress the host innate immune response to facilitate viral replication and pathogenesis. Typical G3BP1+ stress granules (SGs) are usually formed in host cells after virus infection to restrain viral translation and to stimulate innate immunity. Thus, viruses have evolved various mechanisms to inhibit SGs or to repurpose SG components such as G3BP1. Previous studies showed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection inhibited host immunity during the early stage of COVID-19. However, the precise mechanism is not yet well understood. Here we showed that the SARS-CoV-2 nucleocapsid (SARS2-N) protein suppressed the double-stranded RNA (dsRNA)-induced innate immune response, concomitant with inhibition of SGs and the induction of atypical SARS2-N+ /G3BP1+ foci (N+ foci). The SARS2-N protein-induced formation of N+ foci was dependent on the ability of its ITFG motif to hijack G3BP1, which contributed to suppress the innate immune response. Importantly, SARS2-N protein facilitated viral replication by inducing the formation of N+ foci. Viral mutations within SARS2-N protein that impair the formation of N+ foci are associated with the inability of the SARS2-N protein to suppress the immune response. Taken together, our study has revealed a novel mechanism by which SARS-CoV-2 suppresses the innate immune response via induction of atypical N+ foci. We think that this is a critical strategy for viral pathogenesis and has potential therapeutic implications.

Single base-pair resolution analysis of DNA binding motif with MoMotif reveals an oncogenic function of CTCF zinc-finger 1 mutation.

Defining the impact of missense mutations on the recognition of DNA motifs is highly dependent on bioinformatic tools that define DNA binding elements. However, classical motif analysis tools remain limited in their capacity to identify subtle changes in complex binding motifs between distinct conditions. To overcome this limitation, we developed a new tool, MoMotif, that facilitates a sensitive identification, at the single base-pair resolution, of complex, or subtle, alterations to core binding motifs, discerned from ChIP-seq data. We employed MoMotif to define the previously uncharacterized recognition motif of CTCF zinc-finger 1 (ZF1), and to further define the impact of CTCF ZF1 mutation on its association with chromatin. Mutations of CTCF ZF1 are exclusive to breast cancer and are associated with metastasis and therapeutic resistance, but the underlying mechanisms are unclear. Using MoMotif, we identified an extension of the CTCF core binding motif, necessitating a functional ZF1 to bind appropriately. Using a combination of ChIP-Seq and RNA-Seq, we discover that the inability to bind this extended motif drives an altered transcriptional program associated with the oncogenic phenotypes observed clinically. Our study demonstrates that MoMotif is a powerful new tool for comparative ChIP-seq analysis and characterising DNA-protein contacts.

Stress Granule Core Protein-Derived Peptides Inhibit Assembly of Stress Granules and Improve Sorafenib Sensitivity in Cancer Cells.

Upon a variety of environmental stresses, eukaryotic cells usually recruit translational stalled mRNAs and RNA-binding proteins to form cytoplasmic condensates known as stress granules (SGs), which minimize stress-induced damage and promote stress adaptation and cell survival. SGs are hijacked by cancer cells to promote cell survival and are consequently involved in the development of anticancer drug resistance. However, the design and application of chemical compounds targeting SGs to improve anticancer drug efficacy have rarely been studied. Here, we developed two types of SG inhibitory peptides (SIPs) derived from SG core proteins Caprin1 and USP10 and fused with cell-penetrating peptides to generate TAT-SIP-C1/2 and SIP-U1-Antp, respectively. We obtained 11 SG-inducing anticancer compounds from cell-based screens and explored the potential application of SIPs in overcoming resistance to the SG-inducing anticancer drug sorafenib. We found that SIPs increased the sensitivity of HeLa cells to sorafenib via the disruption of SGs. Therefore, anticancer drugs which are competent to induce SGs could be combined with SIPs to sensitize cancer cells, which might provide a novel therapeutic strategy to alleviate anticancer drug resistance.

SARS-CoV-2 Nucleocapsid Protein Antagonizes GADD34-Mediated Innate Immune Pathway through Atypical Foci.

The integrated stress response, especially stress granules (SGs), contributes to host immunity. Typical G3BP1+ stress granules (tSGs) are usually formed after virus infection to restrain viral replication and stimulate innate immunity. Recently, several SG-like foci or atypical SGs (aSGs) with proviral function have been found during viral infection. We have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein induces atypical N+/G3BP1+ foci (N+foci), leading to the inhibition of host immunity and facilitation of viral infection. However, the precise mechanism has not been well clarified yet. In this study, we showed that the SARS-CoV-2 N (SARS2-N) protein inhibits dsRNA-induced growth arrest and DNA damage-inducible 34 (GADD34) expression. Mechanistically, the SARS2-N protein promotes the interaction between GADD34 mRNA and G3BP1, sequestering GADD34 mRNA into the N+foci. Importantly, we found that GADD34 participates in IRF3 nuclear translocation through its KVRF motif and promotes the transcription of downstream interferon genes. The suppression of GADD34 expression by the SARS2-N protein impairs the nuclear localization of IRF3 and compromises the host's innate immune response, which facilitates viral replication. Taking these findings together, our study revealed a novel mechanism by which the SARS2-N protein antagonized the GADD34-mediated innate immune pathway via induction of N+foci. We think this is a critical strategy for viral pathogenesis and has potential therapeutic implications.

YAP suppresses human T-cell leukemia virus type 1 transcription.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 encodes Tax protein that activates transcription from viral long terminal repeats (LTR). Multiple cofactors are involved in the regulation of HTLV-1 transcription via association with Tax. Yes-associated protein (YAP), which is the key effector of Hippo pathway, is elevated and activated in ATL cells. In this study, we reported that YAP protein suppressed Tax activation of HTLV-1 5' LTR but not 3' LTR. The activation of the 5' LTR by Tax was potentiated when YAP was depleted. Moreover, overexpression of YAP repressed HTLV-1 plus-strand viral gene expression and virion production, whereas compromising YAP by RNA inference augmented the expression of HTLV-1 protein. As mechanisms of YAP-mediated viral transcription inhibition, we found that YAP interacted with Tax, and prevented the association between Tax and p300. It finally led to the inhibition of recruitment of Tax to the Tax-responsive element in the 5' LTR of HTLV-1. Taken together, our results demonstrate the negative regulatory function of YAP in Tax activation of HTLV-1 transcription. It may achieve sufficient transcriptional repression to maintain persistent infection and long-term latency of HTLV-1 in the host cells.

Development of FRET and Stress Granule Dual-Based System to Screen for Viral 3C Protease Inhibitors.

3C proteases (3Cpros) of picornaviruses and 3C-like proteases (3CLpros) of coronaviruses and caliciviruses represent a group of structurally and functionally related viral proteases that play pleiotropic roles in supporting the viral life cycle and subverting host antiviral responses. The design and screening for 3C/3CLpro inhibitors may contribute to the development broad-spectrum antiviral therapeutics against viral diseases related to these three families. However, current screening strategies cannot simultaneously assess a compound's cytotoxicity and its impact on enzymatic activity and protease-mediated physiological processes. The viral induction of stress granules (SGs) in host cells acts as an important antiviral stress response by blocking viral translation and stimulating the host immune response. Most of these viruses have evolved 3C/3CLpro-mediated cleavage of SG core protein G3BP1 to counteract SG formation and disrupt the host defense. Yet, there are no SG-based strategies screening for 3C/3CLpro inhibitors. Here, we developed a fluorescence resonance energy transfer (FRET) and SG dual-based system to screen for 3C/3CLpro inhibitors in living cells. We took advantage of FRET to evaluate the protease activity of poliovirus (PV) 3Cpro and live-monitor cellular SG dynamics to cross-verify its effect on the host antiviral response. Our drug screen uncovered a novel role of Telaprevir and Trifluridine as inhibitors of PV 3Cpro. Moreover, Telaprevir and Trifluridine also modulated 3Cpro-mediated physiological processes, including the cleavage of host proteins, inhibition of the innate immune response, and consequent facilitation of viral replication. Taken together, the FRET and SG dual-based system exhibits a promising potential in the screening for inhibitors of viral proteases that cleave G3BP1.

Two-Dimensional Metal-Organic Framework Superstructures from Ice-Templated Self-Assembly.

Here, we report the synthesis of two-dimensional (2D) layered metal-organic framework (MOF) nanoparticle (NP) superstructures via an ice-templating strategy. MOF NP monolayers and bilayers can be obtained by regulating the concentration of colloidal MOF NPs without any external fields during self-assembly. Adjacent polyhedral MOF NPs are packed and aligned through crystalline facets, resulting in the formation of a quasi-ordered array superstructure. The morphology of the MOF layers is well preserved when subjected to pyrolysis, and the obtained carbon NPs have hollow interiors driven by the outward contraction of MOF precursors during pyrolysis. With the advantages of large surface areas, hierarchical porosity, high exposure of active sites, and fast electron transport of the 2D layered structure, the mono- and bilayered carbon NP superstructures show better oxygen reduction activity than isolated carbon particles in alkaline media. Our work demonstrates that ice-templating is a powerful strategy to fabricate superstructures of various MOFs and their derivatives.

Novel Ultrasensitive Photoelectrochemical Cytosensor Based on Hollow CdIn2S4/In2S3 Heterostructured Microspheres for HepG2 Cells Detection and Inhibitor Screening.

Hepatocellular carcinoma is a life-threatening malignant tumor found around the world for its high morbidity and mortality. Therefore, it is of great importance for sensitive analysis of liver cancer cells (HepG2 cells) in clinical diagnosis and biomedical research. To fulfill this demand, hollow CdIn2S4/In2S3 heterostructured microspheres (termed CdIn2S4/In2S3 for clarity) were prepared by a two-step hydrothermal strategy and applied for building a novel photoelectrochemical (PEC) cytosensor for ultrasensitive and accurate detection of HepG2 cells through specific recognition of CD133 protein on the cell surface with the respective aptamer. The optical properties of CdIn2S4/In2S3 were investigated by UV-vis diffuse reflectance spectroscopy (DRS) and PEC technology. By virtue of their appealing PEC characteristics, the resultant PEC sensor exhibited a wider dynamic linear range from 1 × 102 to 2 × 105 cells mL-1 with a lower limit of detection (LOD, 23 cells mL-1), combined by evaluating the expression level of CD133 protein stimulated by metformin as a benchmarked inhibitor. This work opens a valuable and feasible avenue for sensitive detection of diverse tumor cells, holding great potential in early clinical diagnosis and treatment coupled by screening inhibitors.

Novel Aggregation-Enhanced PEC Photosensitizer Based on Electrostatic Linkage of Ionic Liquid with Protoporphyrin IX for Ultrasensitive Detection of Molt-4 Cells.

Nowadays, aggregation quenching of most organic photosensitizers in aqueous media seriously restricts analytical and biomedical applications of photoelectrochemical (PEC) sensors. In this work, an aggregation-enhanced PEC photosensitizer was prepared by electrostatically bonding protoporphyrin IX (PPIX) with an ionic liquid of 1-butyl-3-methylimidazole tetrafluoroborate ([BMIm][BF4]), termed as PPIX-[BMIm] for clarity. The resultant PPIX-[BMIm] showed weak photocurrent in pure dimethyl sulfoxide (DMSO, good solvent), while the PEC signals displayed a 44.1-fold enhancement in a water (poor solvent)/DMSO binary solvent with a water fraction (fw) of 90%. Such PEC-enhanced mechanism was critically studied by electrochemistry and density functional theory (DFT) calculation in some detail. Afterward, a label-free PEC cytosensor was built for ultrasensitive bioassay of acute lymphoblastic leukemia (molt-4) cells by electrodepositing Au nanoparticles (Au NPs) on the PPIX-[BMIm] aggregates and sequential assembly of protein tyrosine kinase (PTK) aptamer DNA (aptDNA). The resultant cytosensor showed a wide linear range (300 to 3 × 105 cells mL-1) with a limit of detection (LOD) as low as 63 cells mL-1. The aggregation-enhanced PEC performance offers a valuable and practical pathway for synthesis of advanced organic photosensitizer to explore its PEC applications in early diagnosis of tumors.

Nonatheromatous Popliteal Artery Disease.

OBJECTIVE: Peripheral artery disease (PAD) is often caused by atherosclerosis. However, causes other than atherosclerosis is often overlooked. Popliteal artery entrapment syndrome (PAES) and popliteal artery adventitial cystic disease (PACD) are two common nonatheromatous causes of claudication and critical limb ischemia. The purpose of this study is to present early results of treatment of PAES and PACD involving the lower limbs. METHODS: From December 2019 to February 2021, 10 patients with PAES underwent surgeries, and 1 patient with PAES received conservative treatment. 2 patients with PACD underwent surgery. Patient data including age, gender, etiology of vascular pathology, diseased vessel, surgical method, and hemodynamic status were collected retrospectively. RESULTS: The mean follow-up duration was 5.64 ± 3.72 months (range, 1-12 months). All patients had their symptoms improved or resolved. The success rate of surgery was 100%, the rate of freedom from reintervention for any reason was 100%. There were no death, bleeding, embolism, or skin ulcers during late follow-up. CONCLUSIONS: PAES and PACD require early diagnosis and intervention, and early surgery may lead to good early- and mid-term results.

A Rat Model of Esophagogastric Anastomotic Stricture.

Esophagogastric anastomosis stricture is one of the most common postoperative complications after esophagectomy; yet, its pathogenesis is still not fully understood, and the treatment and prevention of anastomotic stricture are limited due to the lack of a proper animal model. The insufficient blood supply in the gastric tube is considered a risk factor for postoperative anastomotic strictures. In this study, we used thermal imaging to develop a stable rodent model with esophagogastric anastomotic stricture caused by ischemia. Briefly, 30 male Sprague-Dawley rats have been divided into the control group and the ischemia group. The esophagogastric ischemia anastomosis was performed with the help of intraoperative thermal imaging to identify the poor perfusion area. An unpaired t test with Welch's correction was used to analyze the difference between the two groups. On postoperative day 84, in the control group, no anastomosis stricture was observed, while in the ischemia group, 12 out of 15 animals (80%) developed obvious anastomosis stricture which could not let a 2.7-mm endoscope pass through. The diameter of the anastomosis in the control group and the ischemia group were 2.80 ± 0.15 mm and 1.73 ± 0.44 mm (p < 0.01), respectively (evaluated by endoscopy examination and barium radiography). H&E stain and Masson's trichrome showed that the anastomosis in the ischemia group had more connective tissue hyperplasia and collagen deposition than control group. Thus, this new rat model can be used as a platform to further investigate the potential interventions for prevention of esophagogastric anastomotic stricture.

Photoplethysmogram Recording Length: Defining Minimal Length Requirement from Dynamical Characteristics.

Photoplethysmography is a widely used technique to noninvasively assess heart rate, blood pressure, and oxygen saturation. This technique has considerable potential for further applications-for example, in the field of physiological and mental health monitoring. However, advanced applications of photoplethysmography have been hampered by the lack of accurate and reliable methods to analyze the characteristics of the complex nonlinear dynamics of photoplethysmograms. Methods of nonlinear time series analysis may be used to estimate the dynamical characteristics of the photoplethysmogram, but they are highly influenced by the length of the time series, which is often limited in practical photoplethysmography applications. The aim of this study was to evaluate the error in the estimation of the dynamical characteristics of the photoplethysmogram associated with the limited length of the time series. The dynamical properties were evaluated using recurrence quantification analysis, and the estimation error was computed as a function of the length of the time series. Results demonstrated that properties such as determinism and entropy can be estimated with an error lower than 1% even for short photoplethysmogram recordings. Additionally, the lower limit for the time series length to estimate the average prediction time was computed.

The noncanonical role of EZH2 in cancer.

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2). Dysregulation of EZH2 causes alteration of gene expression and functions, thereby promoting cancer development. The regulatory function of EZH2 varies across different tumor types. The canonical role of EZH2 is gene silencing through catalyzing the trimethylation of lysine 27 of histone H3 (H3K27me3) in a PRC2-dependent manner. Accumulating evidence indicates that EZH2 has an H3K27me3-independent function as a transcriptional coactivator and plays a critical role in cancer initiation, development, and progression. In this review, we summarize the regulation and function of EZH2 and focus on the current understanding of the noncanonical role of EZH2 in cancer.

Fast, regional three-dimensional hybrid (1D-Hadamard 2D-rosette) proton MR spectroscopic imaging in the human temporal lobes.

1 H-MRSI is commonly performed with gradient phase encoding, due to its simplicity and minimal radio frequency (RF) heating (specific absorption rate). Its two well-known main problems-(i) "voxel bleed" due to the intrinsic point-spread function, and (ii) chemical shift displacement error (CSDE) when slice-selective RF pulses are used, which worsens with increasing volume of interest (VOI) size-have long become accepted as unavoidable. Both problems can be mitigated with Hadamard multislice RF encoding. This is demonstrated and quantified with numerical simulations, in a multislice phantom and in five healthy young adult volunteers at 3 T, targeting a 2-cm thick temporal lobe VOI through the bilateral hippocampus. This frequently targeted region (e.g. in epilepsy and Alzheimer's disease) is subject to strong, 1-2 ppm.cm-1 regional B0, susceptibility gradients that can dramatically reduce the signal-to-noise ratio (SNR) and water suppression effectiveness. The chemical shift imaging (CSI) sequence used a 3-ms Shinnar-Le Roux (SLR) 90° RF pulse, acquiring eight steps in the slice direction. The Hadamard sequence acquired two overlapping slices using the same SLR 90° pulses, under twofold stronger gradients that proportionally halved the CSDE. Both sequences used 2D 20 × 20 rosette spectroscopic imaging (RSI) for in-plane spatial localization and both used RF and gradient performance characteristics that are easily met by all modern MRI instruments. The results show that Hadamard spectroscopic imaging (HSI) suffered dramatically less signal bleed within the VOI compared with CSI (<1% vs. approximately 26% in simulations; and 5%-8% vs. >50%) in a phantom specifically designed to test these effects. The voxels' SNR per unit volume per unit time was also 40% higher for HSI. In a group of five healthy volunteers, we show that HSI with in-plane 2D-RSI facilitates fast, 3D multivoxel encoding at submilliliter spatial resolution, over the bilateral human hippocampus, in under 10 min, with negligible CSDE, spectral and spatial contamination and more than 6% improved SNR per unit time per unit volume.

Application of Ag/AgCl Sensor for Chloride Monitoring of Mortar under Dry-Wet Cycles.

An Ag/AgCl electrode used as a corrosion sensor in a reinforced concrete structure isconsidered as having good application prospect. However, its performance under complexconditions, such as dry-wet cycle condition, is not affirmed. In the current study, the performanceof Ag/AgCl as chloride selective electrode in mortar exposed to dry-wet cycle condition wasinvestigated. A simple Ag/AgCl electrode was prepared and fabricated by electrochemicalanodization. These Ag/AgCl electrodes were embedded into a mortar specimen with temperaturesensors, humidity sensors and anode ladder monitoring system (ALS). After 28 d curing time, theupper surface of mortar specimen was wetted (with 5% NaCl solution) and dried regularly. Theobtained results indicate that Ag/AgCl electrode responds to the ingress of chloride ion, sensitively.The chloride ion concentration variation can be reflected by the potential trend. Furthermore, thebalance potential of Ag/AgCl electrodes is influenced by dry-wet cycles. Compared with ALS, itdemonstrates that Ag/AgCl electrodes are more sensitive to chloride. The research provides the keyelement for the specific application of Ag/AgCl electrode for corrosion monitoring in the future.

Hypericin-photodynamic therapy inhibits the growth of adult T-cell leukemia cells through induction of apoptosis and suppression of viral transcription.

BACKGROUND: Adult T-cell leukemia (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). ATL carries a poor prognosis due to chemotherapy resistance. Thus, it is urgent to develop new treatment strategies. Hypericin (HY) is a new-type of photosensitizer in the context of photodynamic therapy (PDT) due to its excellent photosensitizing properties and anti-tumor activities. RESULTS: In the present study, we investigated the efficacy of hypericin in ATL cells. Clinically achievable concentrations of hypericin in association with PDT induced the inhibition of cell proliferation in ATL cell lines with minimal effect on peripheral blood CD4+ T lymphocytes. Moreover, hypericin-PDT treatment caused apoptosis and G2/M phase cell cycle arrest in leukemic cells. Western blot analyses revealed that hypericin-PDT treatment resulted in downregulation of Bcl-2 and enhanced the expression of Bad, cytochrome C, and AIF. Cleavage of caspases-3/-7/-9/-8, Bid, and PARP was increased in hypericin-PDT-treated ATL cells. In a luciferase assay, hypericin-PDT treatment was able to activate the promoter activity of Bax and p53, resulting in enhanced expression of Bax and p53 proteins. Finally, hypericin-PDT treatment suppressed the expression of viral protein HBZ and Tax by blocking the promoter activity via HTLV-1 5'LTR and 3'LTR. CONCLUSIONS: Our results revealed that hypericin-PDT is highly effective against ATL cells by induction of apoptosis and suppression of viral transcription. These studies highlight the promising use of hypericin-PDT as a targeted therapy for ATL.

Activation of Notch1 signaling by HTLV-1 Tax promotes proliferation of adult T-cell leukemia cells.

Human T-cell leukemia virus 1 (HTLV-1), an oncogenic retrovirus, and Notch1 signaling, implicated in tumor formation and progression, are both associated with the development of adult T-cell leukemia (ATL). Here we explored the possibility of a mechanistic link between the two. We observed that the expression of Notch intracellular domain (NICD) was elevated in HTLV-1 infected cell lines. Knocking down of Notch1 in ATL cells repressed cellular proliferation and tumor formation both in vitro and in vivo. As a mechanism for these actions, we found that Tax activated Notch1 signaling by prolonging the half-life of NICD. We then showed that Tax, NICD, and RBP-jκ formed a ternary complex, that Tax enhanced the association of NICD with RBP-jκ, and that Tax, NICD, and RBP-jκ were bound to RBP-jκ-responsive elements. Hence, our results suggest that HTLV-1 promotes cellular proliferation and tumor formation of ATL cells by modulating Notch signaling via a posttranslational mechanism that involves interactions between Tax, NICD, and RBP-jκ.