Maurice Wilkins Center for Molecular Biodiscovery

Auckland, New Zealand

Maurice Wilkins Center for Molecular Biodiscovery

Auckland, New Zealand
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Rodger E.J.,University of Otago | Rodger E.J.,Maurice Wilkins Center for Molecular Biodiscovery | Chatterjee A.,University of Otago | Chatterjee A.,Maurice Wilkins Center for Molecular Biodiscovery
Clinical Epigenetics | Year: 2017

A report of the 6th Epigenomics of Common Diseases Conference held at the Wellcome Genome Campus in Hinxton, Cambridge, UK, on 1–4 November 2016. © 2017, The Author(s).


Ahn A.,University of Otago | Chatterjee A.,University of Otago | Chatterjee A.,Maurice Wilkins Center for Molecular Biodiscovery | Eccles M.R.,University of Otago | Eccles M.R.,Maurice Wilkins Center for Molecular Biodiscovery
Molecular Cancer Therapeutics | Year: 2017

Treatment resistance in metastatic melanoma is a longstanding issue. Current targeted therapy regimes in melanoma largely target the proliferating cancer population, leaving slow-cycling cancer cells undamaged. Consequently, slow-cycling cells are enriched upon drug therapy and can remain in the body for years until acquiring proliferative potential that triggers cancer relapse. Here we overview the molecular mechanisms of slowcycling cells that underlie treatment resistance in melanoma. Three main areas of molecular reprogramming are discussed that mediate slow cycling and treatment resistance. First, a low microphthalmia-associated transcription factor (MITF) dedifferentiated state activates various signaling pathways. This includes WNT5A, EGFR, as well as other signaling activators, such as AXL and NF-kB. Second, the chromatin-remodeling factor Jumonji/ARID domain-containing protein 1B (JARID1B, KDM5B) orchestrates and maintains slow cycling and treatment resistance in a small subpopulation of melanoma cells. Finally, a shift in metabolic state toward oxidative phosphorylation has been demonstrated to regulate treatment resistance in slow-cycling cells. Elucidation of the underlying processes of slow cycling and its utilization by melanoma cells may reveal new vulnerable characteristics as therapeutic targets. Moreover, combining current therapies with targeting slow-cycling subpopulations of melanoma cells may allow for more durable and greater treatment responses. ©2017 American Association for Cancer Research.


Chatterjee A.,University of Otago | Chatterjee A.,Maurice Wilkins Center for Molecular Biodiscovery | Rodger E.J.,University of Otago | Rodger E.J.,Maurice Wilkins Center for Molecular Biodiscovery | And 2 more authors.
Seminars in Cancer Biology | Year: 2017

Since the completion of the first human genome sequence and the advent of next generation sequencing technologies, remarkable progress has been made in understanding the genetic basis of cancer. These studies have mainly defined genetic changes as either causal, providing a selective advantage to the cancer cell (a driver mutation) or consequential with no selective advantage (not directly causal, a passenger mutation). A vast unresolved question is how a primary cancer cell becomes metastatic and what are the molecular events that underpin this process. However, extensive sequencing efforts indicate that mutation may not be a causal factor for primary to metastatic transition. On the other hand, epigenetic changes are dynamic in nature and therefore potentially play an important role in determining metastatic phenotypes and this area of research is just starting to be appreciated. Unlike genetic studies, current limitations in studying epigenetic events in cancer metastasis include a lack of conceptual understanding and an analytical framework for identifying putative driver and passenger epigenetic changes. In this review, we discuss the key concepts involved in understanding the role of epigenetic alterations in the metastatic cascade. We particularly focus on driver epigenetic events, and we describe analytical approaches and biological frameworks for distinguishing between "epi-driver" and "epi-passenger" events in metastasis. Finally, we suggest potential directions for future research in this important area of cancer research. © 2017 The Authors.


PubMed | University of Otago, Maurice Wilkins Center for Molecular Biodiscovery, Capital and Coast District Health Board, Pathlab Bay of Plenty and 2 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

Melanoma, the most aggressive skin cancer type, is responsible for 75% of skin cancer related deaths worldwide. Given that New Zealand (NZ) has the worlds highest melanoma incidence, we sought to determine the frequency of mutations in NZ melanomas in recurrently mutated genes. NZ melanomas were from localities distributed between North (35S-42S) and South Islands (41S-47S). A total of 529 melanomas were analyzed for BRAF exon 15 mutations by Sanger sequencing, and also by Sequenom MelaCarta MassARRAY. While, a relatively low incidence of BRAFV600E mutations (23.4%) was observed overall in NZ melanomas, the incidence of NRAS mutations in South Island melanomas was high compared to North Island melanomas (38.3% vs. 21.9%, P=0.0005), and to The Cancer Genome Atlas database (TCGA) (38.3% vs. 22%, P=0.0004). In contrast, the incidence of EPHB6G404S mutations was 0% in South Island melanomas, and was 7.8% in North Island (P=0.0002). Overall, these data suggest that melanomas from geographically different regions in NZ have markedly different mutation frequencies, in particular in the NRAS and EPHB6 genes, when compared to TCGA or other populations. These data have implications for the causation and treatment of malignant melanoma in NZ.


Dissanayake S.,University of Auckland | Denny W.A.,University of Auckland | Denny W.A.,Maurice Wilkins Center for Molecular Biodiscovery | Gamage S.,University of Auckland | Sarojini V.,University of Auckland
Journal of Controlled Release | Year: 2017

Efficient intracellular trafficking and targeted delivery to the site of action are essential to overcome the current drawbacks of cancer therapeutics. Cell Penetrating Peptides (CPPs) offer the possibility of efficient intracellular trafficking, and, therefore the development of drug delivery systems using CPPs as cargo carriers is an attractive strategy to address the current drawbacks of cancer therapeutics. Additionally, the possibility of incorporating Tumor Targeting Peptides (TTPs) into the delivery system provides the necessary drug targeting effect. Therefore the conjugation of CPPs and/or TTPs with therapeutics provides a potentially efficient method of improving intracellular drug delivery mechanisms. Peptides used as cargo carriers in DDS have been shown to enhance the cellular uptake of drugs and thereby provide an efficient therapeutic benefit over the drug on its own. After providing a brief overview of various drug targeting approaches, this review focusses on peptides as carriers and targeting moieties in drug-peptide covalent conjugates and summarizes the most recent literature examples where CPPs on their own or CPPs together with TTPs have been conjugated to anticancer drugs such as Doxorubicin, Methotrexate, Paclitaxel, Chlorambucil etc. A short section on CPPs used in multicomponent drug delivery systems is also included. © 2017 Elsevier B.V.


Badrinarayanan S.,University of Auckland | Squire C.J.,University of Auckland | Sperry J.,University of Auckland | Brimble M.A.,University of Auckland | Brimble M.A.,Maurice Wilkins Center for Molecular Biodiscovery
Organic Letters | Year: 2017

The total synthesis of both enantiomers of pestalospirane B, 2, has been achieved using a bioinspired tandem dimerization-spiroketalization reaction. Electronic circular dichroism (ECD) and X-ray analysis were used to revise the absolute stereochemistry of the natural product pestalospirane B from 3S, 3′S, 12R, 12′R to its enantiomer 3R, 3′R, 12S, 12′S. © 2017 American Chemical Society.


Watkins H.A.,Maurice Wilkins Center for Molecular Biodiscovery | Baker E.N.,Maurice Wilkins Center for Molecular Biodiscovery
Journal of Bacteriology | Year: 2010

The open reading frame Rv2228c from Mycobacterium tuberculosis is predicted to encode a protein composed of two domains, each with individual functions, annotated through sequence similarity searches. The N-terminal domain is homologous with prokaryotic and eukaryotic RNase H domains and the C-terminal domain with α-ribazole phosphatase (CobC). The N-terminal domain of Rv2228c (Rv2228c/N) and the full-length protein were expressed as fusions with maltose binding protein (MBP). Rv2228c/N was shown to have RNase H activity with a hybrid RNA/DNA substrate as well as double-stranded RNase activity. The full-length protein was shown to have additional CobC activity. The crystal structure of the MBP-Rv2228c/N fusion protein was solved by molecular replacement and refined at 2.25-Å resolution (R = 0.182; Rfree = 0.238). The protein is monomeric in solution but associates in the crystal to form a dimer. The Rv2228c/N domain has the classic RNase H fold and catalytic machinery but lacks several surface features that play important roles in the cleavage of RNA/DNA hybrids by other RNases H. The absence of either the basic protrusion of some RNases H or the hybrid binding domain of others appears to be compensated by the C-terminal CobC domain in full-length Rv2228c. The double-stranded-RNase activity of Rv2228c/N contrasts with classical RNases H and is attributed to the absence in Rv2228c/N of a key phosphate binding pocket. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Chatterjee A.,University of Otago | Chatterjee A.,Maurice Wilkins Center for Molecular Biodiscovery | Eccles M.R.,University of Otago | Eccles M.R.,Maurice Wilkins Center for Molecular Biodiscovery
Genome Biology | Year: 2015

A report of the Keystone Symposia joint meetings on DNA Methylation and Epigenomics held in Keystone, Colorado, USA, 29 March to 3 April, 2015. © 2015 Chatterjee and Eccles et al.; licensee BioMed Central.


Grattan D.R.,University of Otago | Grattan D.R.,Maurice Wilkins Center for Molecular Biodiscovery
Journal of Endocrinology | Year: 2015

The hypothalamic control of prolactin secretion is different from other anterior pituitary hormones, in that it is predominantly inhibitory, by means of dopamine from the tuberoinfundibular dopamine neurons. In addition, prolactin does not have an endocrine target tissue, and therefore lacks the classical feedback pathway to regulate its secretion. Instead, it is regulated by short loop feedback, whereby prolactin itself acts in the brain to stimulate production of dopamine and thereby inhibit its own secretion. Finally, despite its relatively simplename,prolactinhas a broadrange offunctions inthebody, inadditiontoitsdefiningrole in promoting lactation. As such, the hypothalamo-prolactin axis has many characteristics that are quite distinct from other hypothalamo-pituitary systems. This review will provide a brief overview of our current understanding of the neuroendocrine control of prolactin secretion, in particular focusing on the plasticity evident in this system, which keeps prolactin secretion at low levels most of the time, but enables extended periods of hyperprolactinemia when necessary for lactation. Key prolactin functions beyond milk production will be discussed, particularly focusing on the role of prolactin in inducing adaptive responses in multiple different systems to facilitate lactation, and the consequences if prolactin action is impaired. A feature of this pleiotropic activity is that functions thatmay be adaptive in the lactating state might bemaladaptive if prolactin levels are elevated inappropriately. Overall,my goal is to give aflavourofboth the history and current state of thefield ofprolactin neuroendocrinology, and identify some exciting new areas of research development. © 2015 Society for Endocrinology.


Cognard E.,University of Auckland | Dargaville C.G.,University of Auckland | Hay D.L.,Maurice Wilkins Center for Molecular Biodiscovery | Hay D.L.,University of Auckland | And 2 more authors.
Biochemical Journal | Year: 2013

Pancreatic β-cells are highly responsive to changes in glucose, but the mechanisms involved are only partially understood. There is increasing evidence that the β-catenin signalling pathway plays an important role in regulating β-cell function, but the mechanisms regulating β-catenin signalling in these cells is not well understood. In the present study we showthat β-catenin levels and downstream signalling are regulated by changes in glucose levels in INS-1E and β-TC6-F7 β-cell models. We found a glucose-dependent increase in levels of β-catenin in the cytoplasm and nucleus of INS-1E cells. Expression of cyclin D1 also increased with glucose and required the presence of β-catenin. This was associated with an increase in phosphorylation of β-catenin on Ser552, which is known to stabilize the molecule and increase its transcriptional activity. In a search for possible signalling intermediates we found forskolin and cell-permeable cAMP analogues recapitulated the glucose effects, suggesting a role for cAMP and PKA (cAMP-dependent protein kinase/protein kinase A) downstream of glucose. Furthermore, glucose caused sustained increases in cAMP. Two different inhibitors of adenylate cyclase and PKA signalling blocked the effects of glucose, whereas siRNA (small interfering RNA) knockdown of PKA blocked the effects of glucose on β-catenin signalling. Finally, reducing β-catenin levels with either siRNA or pyrvinium impaired glucose- and KCl-stimulated insulin secretion. Taken together the results of the present study define a pathway by which changes in glucose levels can regulate β-catenin using a mechanism which involves cAMP production and the activation of PKA. This identifies a pathway that may be important in glucose-dependent regulation of gene expression and insulin secretion in β-cells. © The Authors Journal compilation © 2013 Biochemical Society.

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