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A+ Network, Childrens Medical Research Institute and Mt Sinai Hospital | Date: 2017-01-25

Provided herein are methods for facilitating or inducing stable transgene integration and expression in a proliferating cell, comprising administering to the cell (i) a recombinant AAV (rAAV) vector comprising the transgene flanked by transposon-derived inverted terminal repeat sequences, which sequences are in turn flanked by AAV-derived inverted terminal repeat regions, and (ii) a source of a transposase that recognises said transposon-derived inverted terminal repeat sequences and directs the genomic integration of the transgene into the genome of the proliferating cell. Also provided are methods and transgene delivery systems for the treatment or prevention of diseases affecting, associated with or characterised by proliferating cells, including paediatric liver diseases, bone marrow diseases and cancer.

Pera M.F.,University of Southern California | Tam P.P.L.,Childrens Medical Research Institute | Tam P.P.L.,University of Sydney
Nature | Year: 2010

During early mammalian development, as the pluripotent cells that give rise to all of the tissues of the body proliferate and expand in number, they pass through transition states marked by a stepwise restriction in developmental potential and by changes in the expression of key regulatory genes. Recent findings show that cultured stem-cell lines derived from different stages of mouse development can mimic these transition states. They further reveal that there is a high degree of heterogeneity and plasticity in pluripotent populations in vitro and that these properties are modulated by extrinsic signalling. Understanding the extrinsic control of plasticity will guide efforts to use human pluripotent stem cells in research and therapy. © 2010 Macmillan Publishers Limited. All rights reserved.

The General Hospital Corporation and Childrens Medical Research Institute | Date: 2010-05-21

There is provided a method for promoting dynamin ring formation and/or maintenance of dynamin rings in a cell, comprising treating the cell with an effective amount of a dynamin ring stabilizer, or a prodrug or pharmaceutically acceptable salt of the dynamin ring stabilizer. The maintenance or accumulation of dynamin ring formation has particular application in the prophylaxis or treatment of a kidney disease or condition characterized by proteinuria. A dynamin ring stabilizer can be any agent that interacts with dynamin to promote dynamin ring assembly and/or inhibit dynamin ring disassembly. There are also provided methods for prophylaxis or treatment of podocyte dysfunction and/or maintaining or inducing actin cytoskeleton formation in a cell utilizing dynamin ring stabilizers, and for screening a test agent for use as a dynamin ring stabilizer.

Cesare A.J.,Childrens Medical Research Institute | Cesare A.J.,University of Sydney | Cesare A.J.,Salk Institute for Biological Studies | Reddel R.R.,Childrens Medical Research Institute | Reddel R.R.,University of Sydney
Nature Reviews Genetics | Year: 2010

Unlimited cellular proliferation depends on counteracting the telomere attrition that accompanies DNA replication. In human cancers this usually occurs through upregulation of telomerase activity, but in 10ĝ€"15% of cancers ĝ€" including some with particularly poor outcome ĝ€" it is achieved through a mechanism known as alternative lengthening of telomeres (ALT). ALT, which is dependent on homologous recombination, is therefore an important target for cancer therapy. Although dissection of the mechanism or mechanisms of ALT has been challenging, recent advances have led to the identification of several genes that are required for ALT and the elucidation of the biological significance of some phenotypic markers of ALT. This has enabled development of a rapid assay of ALT activity levels and the construction of molecular models of ALT. © 2010 Macmillan Publishers Limited. All rights reserved.

Arkell R.M.,Australian National University | Fossat N.,Childrens Medical Research Institute | Fossat N.,University of Sydney | Tam P.P.L.,Childrens Medical Research Institute | Tam P.P.L.,University of Sydney
Current Opinion in Genetics and Development | Year: 2013

Embryonic development and adult homeostasis are dependent upon the coordinated action of signal transduction pathways such as the Wnt signalling pathway which is used iteratively during these processes. In the early post-implantation mouse embryo, Wnt/β-catenin signalling activity plays a critical role in the formation of the primitive streak, progression of gastrulation and tissue patterning in the anterior-posterior axis. The net output of the signalling pathway is influenced by the delivery and post-translational modification of the ligands, the counteracting activities of the activating components and the negative modulators, and the molecular interaction of β-catenin, TCF and other factors regulating the transcription of downstream target genes. © 2013 Elsevier Ltd.

Henson J.D.,Childrens Medical Research Institute | Reddel R.R.,Childrens Medical Research Institute | Reddel R.R.,University of Sydney
FEBS Letters | Year: 2010

Alternative Lengthening of Telomeres (ALT) activity can be deduced from the presence of telomere length maintenance in the absence of telomerase activity. More convenient assays for ALT utilize phenotypic markers of ALT activity, but only a few of these assays are potentially definitive. Here we assess each of the current ALT assays and their implications for understanding the ALT mechanism. We also review the clinical situations where availability of an ALT activity assay would be advantageous. The prevalence of ALT ranges from 25% to 60% in sarcomas and 5% to 15% in carcinomas. Patients with many of these types of ALT[+] tumors have a poor prognosis. © 2010 Federation of European Biochemical Societies.

Double strand break (DSB) repair is suppressed during mitosis because RNF8 and downstream DNA damage response (DDR) factors, including 53BP1, do not localize to mitotic chromatin. Discovery of the mitotic kinase-dependent mechanism that inhibits DSB repair during cell division was recently reported. It was shown that restoring mitotic DSB repair was detrimental, resulting in repair dependent genome instability and covalent telomere fusions. The telomere DDR that occurs naturally during cellular aging and in cancer is known to be refractory to G2/M checkpoint activation. Such DDR-positive telomeres, and those that occur as part of the telomere-dependent prolonged mitotic arrest checkpoint, normally pass through mitosis without covalent ligation, but result in cell growth arrest in G1 phase. The discovery that suppressing DSB repair during mitosis may function primarily to protect DDR-positive telomeres from fusing during cell division reinforces the unique cooperation between telomeres and the DDR to mediate tumor suppression. © 2014 The Author. Bioessays published by WILEY Periodicals, Inc.

Chircop M.,Childrens Medical Research Institute
Small GTPases | Year: 2014

Rho GTPases regulate a diverse range of cellular functions primarily through their ability to modulate microtubule dynamics and the actin-myosin cytoskeleton. Both of these cytoskeletal structures are crucial for a mitotic cell division. Specifically, their assembly and disassembly is tightly regulated in a temporal manner to ensure that each mitotic stage occurs in the correct sequential order and not prematurely until the previous stage is completed. Thus, it is not surprising that the Rho GTPases, RhoA, and Cdc42, have reported roles in several stages of mitosis: cell cortex stiffening during cell rounding, mitotic spindle formation, and bi-orient attachment of the spindle microtubules to the kinetochore and during cytokinesis play multiple roles in establishing the division plane, assembly, and activation of the contractile ring, membrane ingression, and abscission. Here, I review the molecular mechanisms regulating the spatial and temporal activation of RhoA and Cdc42 during mitosis, and how this is critical for mitotic progression and completion.

Engholm-Keller K.,University of Southern Denmark | Engholm-Keller K.,Childrens Medical Research Institute | Larsen M.R.,University of Southern Denmark
Proteomics | Year: 2013

Phosphorylation, the reversible addition of a phosphate group to amino acid side chains of proteins, is a fundamental regulator of protein activity, stability, and molecular interactions. Most cellular processes, such as inter- and intracellular signaling, protein synthesis, degradation, and apoptosis, rely on phosphorylation. This PTM is thus involved in many diseases, rendering localization and assessment of extent of phosphorylation of major scientific interest. MS-based phosphoproteomics, which aims at describing all phosphorylation sites in a specific type of cell, tissue, or organism, has become the main technique for discovery and characterization of phosphoproteins in a nonhypothesis driven fashion. In this review, we describe methods for state-of-the-art MS-based analysis of protein phosphorylation as well as the strategies employed in large-scale phosphoproteomic experiments with focus on the various challenges and limitations this field currently faces. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Speidel D.,Childrens Medical Research Institute
Trends in Cell Biology | Year: 2010

Apoptosis induced by p53 is firmly established as a central mechanism of tumour suppression. In addition to its complex functions as a nuclear transcription factor, p53 can act in the cytosol and mitochondria to promote apoptosis through transcription-independent mechanisms. Recent studies have shown that physical and functional interactions of p53 with various members of the Bcl-2 family provide the basis for this alternative route of p53-mediated cell death. However, different models of how these interactions promote apoptosis have been proposed. This review focuses on the mechanisms, regulation and physiological roles of transcription-independent p53 activities and highlights recent findings suggesting that the utilisation of these activities provides a promising alternative strategy for p53-based cancer therapy. © 2009 Elsevier Ltd. All rights reserved.

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