Molecular mechanisms of mitotic progression and the anti-cancer properties of anti-mitotic agents

Summary

The major focus of my laboratory is to precisely define the mechanisms regulating a mitotic cell division. Understanding the molecular regulation of mitosis will provide insight into cancer biology mechanisms. Despite the identification of many mitotic proteins, the molecular mechanisms driving mitotic progression and how these proteins cooperatively function to complete mitosis in mammalian cells is not fully understood. Importantly, cell division errors increase the oncogenic potential of a cell, and cancer cells frequently harbor an altered mitotic program. Thus, understanding this basic biological process underpins our understanding of cancer biology mechanisms, which can lead to the identification of druggable targets to treat this disease. My work has enabled me to develop a well respected national and international reputation in this field. My lab’s focus and thus PhD projects are available in the following two areas:

1) Basic research: molecular mechanisms of mitotic progression and completion
2)Translational biology: drug discovery of new anti-mitotic compounds for cancer treatment

Supervisor(s)

Dr Megan Chircop (nee Fabbro)

Research Location

Westmead - Childrens Medical Research Institute

Program Type

PHD

Synopsis

1) Basic research: molecular mechanisms of mitotic progression and completion
Cell division (mitosis) results in the generation of two independent daughter cells. It is the final phase of the cell cycle and consists of six distinct stages – prophase, prometaphase, metaphase, anaphase, telophase and cytokinesis. Progression through these phases is highly regulated and is thought to involve membrane trafficking proteins, such as those required for endocytosis. However, their role is poorly understood and it is not known if these proteins function in an endocytic-dependent or –independent manner. We and others have reported on the mitotic roles of the endocytic proteins, dynamin II (dynII) and clathrin, and both participate in this process independent of each other and in a non-endocytic-dependent manner. In addition to dynII and clathrin, we have since discovered 8 other endocytic proteins that are associated with dynamin for clathrin-mediated or bulk endocytosis, are also required for mitotic progression and completion. These proteins appear to function during cytokinesis in an endocytic-dependent manner but during earlier stages of mitosis in an endocytic-independent manner. This represents a significantly new and broad concept in mitosis that endocytic proteins are intimately linked with mitosis. We have generated tagged-expression constructs and siRNA molecules targeting each endocytic protein. Thus, we are now in a unique position and research projects in this area aim to ascribe new roles to this subset of endocytic proteins. The outcomes of the research will be an improved understanding of the molecular mechanisms of mitosis and insight into the pathways that regulate this process. The results will directly contribute to improved understanding of cancer progression.

2) Translational biology: drug discovery of new anti-mitotic compounds for cancer treatment
Drugs that disrupt mitotic progression are commonly referred to as ‘anti-mitotics’ and are extensively used for cancer treatment. Classical ‘anti-mitotic’ chemotherapeutics used in the clinic target microtubules and include taxanes and vinca alkaloids. Despite success in the clinic, drug resistance and toxicity have partly limited their effectiveness, due to the broad role of tubulin in the cytoskeleton of normal and non-dividing cells. A new class of anti-mitotics specifically target mitotic proteins such as aurora kinase, polo-like kinase, kinesin spindle protein. Such inhibitors are being characterised as potential chemotherapeutic agents since several induce mitotic failure, leading to apoptotic cell death in cancer cells and xenograft mouse cancer models. These inhibitors are predicted to be more efficacious and many are currently in cancer clinical trials. We are the world leaders in the development of dynamin and clathrin inhibitors and have shown that they also possess anti-mitotic and anti-cancer properties that are analogous to other mitotic inhibitors due to their ability to cause cell death following mitotic failure. We have also shown proof-of-concept that dynamin inhibition is a valid anti-cancer therapeutic approach as dynamin inhibitors reduce tumour volume in an in vivo mouse model of brain cancer. Research projects in this area will not only provide proof-of-concept that dynamin and clathrin are also valid targets for the development of inhibitors as chemotherapeutic agents but also identify our most efficacious dynamin and clathrin inhibitors that could be pursued to progress into human clinical trials for the treatment of cancer.

Additional Information

The Children’s Medical Research Institute (CMRI) is an award-winning state-of-the-art medical research facility, with over 100 full-time scientists dedicated to researching the genes and proteins important for health and human development. The CMRI is supported in part by its key fundraiser Jeans for Genes®. Our scientists are internationally recognised research leaders and foster excellence in postgraduate training. CMRI graduates are highly sought after nationally and internationally. CMRI is located at Westmead, a major hub for research and medicine in NSW, and is affiliated with the University of Sydney. Easy to access by public transport. Projects are multi-disciplinary with training in molecular and cellular biology techniques, with some involving mass spectrometry, proteomics, protein-protein interactions, transgenic animals or live cell imaging. We are looking for top quality students who can prove a dedicated interest and enthusiasm for scientific research.

Candidates may apply for a CMRI PhD scholarship, which exceeds the Australian Postgraduate Awards and NHMRC scholarships in value; visit the CMRI website for details.

Projects in the Cell Cycle Unit involve cell biology, molecular biology and biochemistry techniques such as cell culture, immunofluorescence and time-lapse live cell microscopy, protein-protein interaction assays and detection and functional analysis of post-translational modifications as well as anti-cancer drug analysis in cells and in vivo.

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Keywords

mitosis, cytokinesis failure, aneuploidy, protein phosphorylation, endocytic proteins, dynamin, mitotic inhibitory drugs, cell cycle, Cancer, the final stage of mitosis, cytokinesis, cell signaling

Opportunity ID

The opportunity ID for this research opportunity is: 1013