Upregulation of Id1 by Epstein-Barr Virus-encoded LMP1 confers resistance to TGFβ-mediated growth inhibition

BACKGROUND: Epstein-Barr virus (EBV)-encoded LMP1 protein is commonly expressed in nasopharyngeal carcinoma (NPC). LMP1 is a prime candidate for driving tumourigenesis given its ability to activate multiple signalling pathways and to alter the expression and activity of variety of downstream targets. Resistance to TGFβ-mediated cytostasis is one of the growth transforming effects of LMP1. Of the downstream targets manipulated by LMP1, the induction of Id1 and inactivation of Foxo3a appear particularly relevant to LMP1-mediated effects. Id1, a HLH protein is implicated in cell transformation and plays a role in cell proliferation, whilst Foxo3a, a transcription factor controls cell integrity and homeostasis by regulating apoptosis. The mechanism(s) by which LMP1 induces these effects have not been fully characterised. RESULTS: In this study, we demonstrate that the ability of LMP1 to induce the phosphorylation and inactivation of Foxo3a is linked to the upregulation of Id1. Furthermore, we show that the induction of Id1 is essential for the transforming function of LMP1 as over-expression of Id1 increases cell proliferation, attenuates TGFβ-SMAD-mediated transcription and renders cells refractory to TGFβ-mediated cytostasis. Id1 silencing in LMP1-expressing epithelial cells abolishes the inhibitory effect of LMP1 on TGFβ-mediated cell growth arrest and reduces the ability of LMP1 to attenuate SMAD transcriptional activity. In response to TGFβ stimulation, LMP1 does not abolish SMAD phosphorylation but inhibits p21 protein expression. In addition, we found the induction of Id1 in LMP1-expressing cells upon stimulation by TGFβ. We provide evidence that LMP1 suppresses the transcriptional repressor ATF3, possibly leading to the TGFβ-induced Id1 upregulation. CONCLUSION: The current data provide novel information regarding the mechanisms by which LMP1 suppresses TGFβ-induced cytostasis, highlighting the importance of Id1 in LMP1 mediated cell transformatio

Contralateral Cerebro-Cerebellar White Matter Pathways for Verbal Working Memory: A Combined Diffusion Spectrum Imaging and fMRI Study

Diffusion spectrum imaging was employed to establish structural connectivity between cerebro-cerebellar regions co-activated during verbal working memory. IFG, IPL, pons, thalamus, superior cerebellum and inferior cerebellum were used as seed points to reconstruct the white matter cerebro-cerebellar circuitry. The reconstructed pathways were examined further to establish the relationship between structural and effective connectivity as well as the relationship between structural connectivity and verbal working memory performance. It was found that structural connectivity is indirectly related to effective connectivity but does not predict it. Additionally, it was demonstrated that the integrity of the ponto-cerebellar tract is an important factor in explaining individual differences in verbal working memory. The findings of the study furthered our understanding of the relationship between structural and functional connectivity and provided insight to the variability in verbal working memory performance

A novel Hsp90 inhibitor AT13387 induces senescence in EBV-positive nasopharyngeal carcinoma cells and suppresses tumor formation

Background: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy strongly associated with Epstein-Barr virus (EBV). AT13387 is a novel heat shock protein 90 (Hsp90) inhibitor, which inhibits the chaperone function of Hsp90 and reduces expression of Hsp90-dependent client oncoproteins. This study aimed to evaluate both the in vitro and in vivo antitumor effects of AT13387 in the EBV-positive NPC cell line C666-1.Results: Our results showed that AT13387 inhibited C666-1 cell growth and induced cellular senescence with the downregulation of multiple Hsp90 client oncoproteins EGFR, AKT, CDK4, and restored the protein expression of negative cell cycle regulator p27. We also studied the ability of AT13387 to restore p27 expression by downregulation of AKT and the p27 ubiquitin mediator, Skp2, using AKT inhibitor and Skp2 siRNA. In the functional study, AT13387 inhibited cell migration with downregulation of a cell migration regulator, HDAC6, and increased the acetylation and stabilization of α-tubulin. We also examined the effect of AT13387 on putative cancer stem cells (CSC) by 3-D tumor sphere formation assay. AT13387 effectively reduced both the number and size of C666-1 tumor spheres with decreased expression of NPC CSC-like markers CD44 and SOX2. In the in vivo study, AT13387 significantly suppressed tumor formation in C666-1 NPC xenografts.Conclusion: AT13387 suppressed cell growth, cell migration, tumor sphere formation and induced cellular senescence on EBV-positive NPC cell line C666-1. Also, the antitumor effect of AT13387 was demonstrated in an in vivo model. This study provided experimental evidence for the preclinical value of using AT13387 as an effective antitumor agent in treatment of NPC. © 2013 Chan et al.; licensee BioMed Central Ltd.published_or_final_versio

Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery

published_or_final_versio

Radio Astronomy

Contains reports on isx research projects.National Aeronautics and Space Administration, Langley Research Center (Contract NAS1-10693)National Science Foundation (Grant GP-21348)National Science Foundation (Grant GP-14589)California Institute of Technology Contract 952568Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DAAB07-71-C-030

A novel oxygen carrier 'YQ23' suppresses the liver tumor metastasis by decreasing circulating endothelial progenitor cells and regulatory T cells

published_or_final_versio

Radio Astronomy

Contains research objectives, summary of research and reports on five research projects.National Aeronautics and Space Administration (Grant NGL 22-009-016)National Aeronautics and Space Administration (Grant NGR 22-009-421)Langley Research Center Contract NASI-10693National Science Foundation (Grants GP-20769)National Science Foundation (Grants GP-21348)National Science Foundation (Grants GP-14589)California Institute of Technology Contract 952568Sloan Fund for Basic Research (M.I.T., Grant 241

Microwave and Millimeter Wave Techniques

Contains reports on three research projects.Joint Services Electronics Program (Contract DAAB07-71-C-0300)National Science Foundation (Grant GP-40485X