TRF2-Mediated Stabilization of hREST4 Is Critical for the Differentiation and Maintenance of Neural Progenitors

Abstract Telomere repeat binding factor 2 (TRF2) is a component of the shelterin complex that is known to bind and protect telomeric DNA, yet the detection of TRF2 in extra-telomeric regions of chromosomes suggests other roles for TRF2 besides telomere protection. Here, we demonstrate that TRF2 plays a critical role in antagonizing the repressive function of neuron-restrictive silencer factor, also known as repressor element-1 silencing transcription factor (REST), during the neural differentiation of human embryonic stem cells (hESCs) by enhancing the expression of a truncated REST splice isoform we term human REST4 (hREST4) due to its similarity to rodent REST4. We show that TRF2 is specifically upregulated during hESC neural differentiation concordantly with an increase in the expression of hREST4 and that both proteins are highly expressed in NPCs. Overexpression of TRF2 in hESCs increases hREST4 levels and induces their neural differentiation, whereas TRF2 knockdown in hESCs and NPCs reduces hREST4 expression, hindering their ability to differentiate to the neural lineage. Concurrently, we show that TRF2 directly interacts with the C-terminal of hREST4 through its TRF2 core binding motif [F/Y]xL, protecting hREST4 from ubiquitin-mediated proteasomal degradation and consequently furthering neural induction. Thus, the TRF2-mediated counterbalance between hREST4 and REST is vital for both the generation and maintenance of NPCs, suggesting an important role for TRF2 in both neurogenesis and function of the central nervous system. Stem Cells  2014;32:2111–2122</jats:p

Nuclear localisation of Aurora-A: its regulation and significance for Aurora-A functions in cancer.

The Aurora-A kinase regulates cell division, by controlling centrosome biology and spindle assembly. Cancer cells often display elevated levels of the kinase, due to amplification of the gene locus, increased transcription or post-translational modifications. Several inhibitors of Aurora-A activity have been developed as anti-cancer agents and are under evaluation in clinical trials. Although the well-known mitotic roles of Aurora-A point at chromosomal instability, a hallmark of cancer, as a major link between Aurora-A overexpression and disease, recent evidence highlights the existence of non-mitotic functions of potential relevance. Here we focus on a nuclear-localised fraction of Aurora-A with oncogenic roles. Interestingly, this pool would identify not only non-mitotic, but also kinase-independent functions of the kinase. We review existing data in the literature and databases, examining potential links between Aurora-A stabilisation and localisation, and discuss them in the perspective of a more effective targeting of Aurora-A in cancer therapy

Sensitivity and specificity of Epstein-Barr virus IgA titer in the diagnosis of nasopharyngeal carcinoma: A three-year institutional review

Background. IgA antibody titers to the Epstein-Barr virus (EBV) viral capsid antigen (EBV IgA-VCA) and to the EBV early antigen (EBV IgA-EA) are used to screen for nasopharyngeal carcinoma (NPC). This study evaluates the sensitivity and specificity of EBV IgA-VCA and EBV IgA-EA titers in screening patients for NPC and in those diagnosed with NPC at our institution. Methods. NPC status was determined for all patients who had their EBV IgA-VCA and EBV-IgA EA titers measured over a 3-year period, and the sensitivity and specificity were calculated. Results. Five thousand one hundred ninety-six samples were analyzed. NPC was diagnosed in 215 patients. The sensitivity and specificity of a raised EBV IgA-VCA titer (≥1:5) for diagnosing NPC were 89% and 80%, respectively, with a raised EbV IgA-EA titer (≥1:5) having a sensitivity and specificity of 63% and 97%, respectively. Conclusions. Although the EBV IgA-VCA titer is sensitive for the diagnosis of NPC, it should not be used as the sole means of screening for NPC in a population in which NPC is endemic. © 2004 Wiley Periodicals, Inc.link_to_subscribed_fulltex