Notch and NOXA-related pathways in melanoma cells

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

FGFR2 as a molecular target in endometrial cancer

Although molecularly targeted therapies have been effective in some cancer types, no targeted therapy is approved for use in endometrial cancer. The recent identification of activating mutations in fibroblast growth factor receptor 2 (FGFR2) in endometrial tumors has generated a new avenue for the development of targeted therapeutic agents. The majority of the mutations identified are identical to germline mutations in FGFR2 and FGFR3 that cause craniosynostosis and hypochondroplasia syndromes and result in both ligand-independent and ligand-dependent receptor activation. Mutations that predominantly occur in the endometrioid subtype of endometrial cancer, are mutually exclusive with KRAS mutation, but occur in the presence of PTEN abrogation. In vitro studies have shown that endometrial cancer cell lines with activating FGFR2 mutations are selectively sensitive to a pan-FGFR inhibitor, PD173074. Several agents with activity against FGFRs are currently in clinical trials. Investigation of these agents in endometrial cancer patients with activating FGFR2 mutations is warranted.

p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation

p53 is the central member of a critical tumor suppressor pathway in virtually all tumor types, where it is silenced mainly by missense mutations. In melanoma, p53 predominantly remains wild type, thus its role has been neglected. To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the 'high-p53'Mdm4+/- mouse to the well-established TP-ras0/+ murine melanoma progression model. After treatment with the carcinogen dimethylbenzanthracene (DMBA), TP-ras0/+ mice on the Mdm4+/- background developed fewer tumors with a delay in the age of onset of melanomas compared to TP-ras0/+ mice. Furthermore, we observed a dramatic decrease in tumor growth, lack of metastasis with increased survival of TP-ras0/+: Mdm4+/- mice. Thus, p53 effectively prevented the conversion of small benign tumors to malignant and metastatic melanoma. p53 activation in cultured primary melanocyte and melanoma cell lines using Nutlin-3, a specific Mdm2 antagonist, supported these findings. Moreover, global gene expression and network analysis of Nutlin-3-treated primary human melanocytes indicated that cell cycle regulation through the p21WAF1/CIP1 signaling network may be the key anti-melanomagenic activity of p53.

Targeting mutant fibroblast growth factor receptors in cancer

Fibroblast growth factor receptors (FGFRs) play diverse roles in the control of cell proliferation, cell differentiation, angiogenesis and development. Activating the mutations of FGFRs in the germline has long been known to cause a variety of skeletal developmental disorders, but it is only recently that a similar spectrum of somatic FGFR mutations has been associated with human cancers. Many of these somatic mutations are gain-of-function and oncogenic and create dependencies in tumor cell lines harboring such mutations. A combination of knockdown studies and pharmaceutical inhibition in preclinical models has further substantiated genomically altered FGFR as a therapeutic target in cancer, and the oncology community is responding with clinical trials evaluating multikinase inhibitors with anti-FGFR activity and a new generation of specific pan-FGFR inhibitors.

Computational approaches for modelling intrinsic noise and delays in genetic regulatory networks

This chapter focuses on the interactions and roles between delays and intrinsic noise effects within cellular pathways and regulatory networks. We address these aspects by focusing on genetic regulatory networks that share a common network motif, namely the negative feedback loop, leading to oscillatory gene expression and protein levels. In this context, we discuss computational simulation algorithms for addressing the interplay of delays and noise within the signaling pathways based on biological data. We address implementational issues associated with efficiency and robustness. In a molecular biology setting we present two case studies of temporal models for the Hes1 gene (Monk, 2003; Hirata et al., 2002), known to act as a molecular clock, and the Her1/Her7 regulatory system controlling the periodic somite segmentation in vertebrate embryos (Giudicelli and Lewis, 2004; Horikawa et al., 2006).

Stochastic simulation for spatial modelling of dynamic process in a living cell

One of the fundamental motivations underlying computational cell biology is to gain insight into the complicated dynamical processes taking place, for example, on the plasma membrane or in the cytosol of a cell. These processes are often so complicated that purely temporal mathematical models cannot adequately capture the complex chemical kinetics and transport processes of, for example, proteins or vesicles. On the other hand, spatial models such as Monte Carlo approaches can have very large computational overheads. This chapter gives an overview of the state of the art in the development of stochastic simulation techniques for the spatial modelling of dynamic processes in a living cell.

Modeling intrinsic noise and delays in chemical kinetics of coupled autoregulated oscillating cells

Delays are an important feature in temporal models of genetic regulation due to slow biochemical processes, such as transcription and translation. In this paper, we show how to model intrinsic noise effects in a delayed setting by either using a delay stochastic simulation algorithm (DSSA) or, for larger and more complex systems, a generalized Binomial τ-leap method (Bτ-DSSA). As a particular application, we apply these ideas to modeling somite segmentation in zebra fish across a number of cells in which two linked oscillatory genes (her1 and her7) are synchronized via Notch signaling between the cells.

Computer-intensive simulations for cellular models

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Peer partnership to enhance scholarship of teaching : a case study

This paper reports on the outcomes of a peer partnership program trialled at the Queensland University of Technology (QUT), Australia. The program was designed based on a community of practice methodology to bring together academic staff for the purpose of advancing teaching practice. The program encouraged professional and supportive environments for the purpose of critical reflection and personal development. The belief was that quality teaching is core business and vital to university organisational goals. Peer partnership programs support improvement in teaching and learning. Participants in the program reported the program enhanced their commitment and insight into teaching and that there is willingness to be involved if supported by colleagues and an organisation. Feedback from participants in the program was positive and outcomes arising from the QUT Peer Partnership Project were the development of an online peer partner tool-kit, staff development training, an instructional DVD and integration of the project goals within QUT staff development programs.

Regulating greenhouse gas emissions from coal mining activities in the context of climate change

Current approaches to the regulation of coal mining activities in Australia have facilitated the extraction of substantial amounts of coal and coal seam gas. The regulation of coal mining activities must now achieve the reduction or mitigation of greenhouse gas emissions in order to address the challenge of climate change and achieve ecologically sustainable development. Several legislative mechanisms currently exist which appear to offer the means to bring about the reduction or mitigation of greenhouse gas emissions from coal mining activities, yet Australia’s emissions from coal mining continue to rise. This article critiques these existing legislative mechanisms and presents recommendations for reform.

A formative evaluation of the Stronger Smarter Learning Communities Project. 2011 report.

This report is a formative evaluation of the operations of the DEEWR funded Stronger Smarter Learning Community (SSLC) project from September 2009 to July 2011. It is undertaken by an independent team of researchers from Queensland University of Technology, the University of Newcastle and Harvard University. It reports on findings from: documentary analysis; qualitative case studies of SSLC Hub schools; descriptive, multivariate and multilevel analysis of survey data from school leaders and teachers from SSLC Hub and Affiliate schools and from a control group of non-SSLC schools; and multilevel analysis of school-level data on SSLC Hubs, Affiliates and ACARA like-schools. Key findings from this work are that: • SSLC school leaders and teachers are reporting progress in changing school ethos around issues of: recognition of Indigenous identity, Indigenous leadership, innovative approaches to staffing and school models, Indigenous community engagement and high expectations leadership; • Many Stronger Smarter messages are reportedly having better uptake in schools with high percentages of Indigenous students; • There are no major or consistent patterns of differences between SSLC and non-SSLC schools in teacher and school leader self-reports of curriculum and pedagogy practices; and • There is no evidence to date that SSLC Hubs and Affiliates have increased attendance or increased achievement gains compared to ACARA like-schools. Twenty-one months is relatively early in this school reform project. Hence the major focus of subsequent reports will be on the documentation of comparative longitudinal gains in achievement tests and improved attendance. The 2011 and 2012 research also will model the relationships between change in school ethos/climate, changed Indigenous community relations, improved curriculum/pedagogy, and gains in Indigenous student achievement, attendance and outcomes. The key challenge for SSLC and the Stronger Smarter approach will be whether it can systematically generate change and reform in curriculum and pedagogy practices that can be empirically linked to improved student outcomes.

Editorial : Decolonising action research (Electronic Version)

This edition of the ALAR Action learning action research journal aims to capture some of the current dilemmas, solutions and actions researchers experience in the decolonising space. This collection of papers demonstrates that researchers are not only undertaking action research with and within Indigenous and non-Indigenous contexts, but that they are doing so in exciting and dynamic ways across a diversity of situations. First we will address some of the literature on decolonisation. Then we will explain how this specific edition of the Journal came to fruition and aspects of action research.