Great news, we have had a co-author review published in the Journal of Molecular and Cellular Biology.
You can check out the full review here.
The major cause of death from breast cancer is not the primary tumour, but relapsing, drug-resistant, metastatic disease. Identifying factors that contribute to aggressive cancer offers important leads for therapy. Inherent defense against carcinogens depends on the individual molecular make-up of each person. Important molecular determinants of these responses are under the control of the mouse double minute (MDM) family: comprised of the proteins MDM2 and MDM4. In normal, healthy adult cells, the MDM family functions to critically regulate measured, cellular responses to stress and subsequent recovery. Proper function of the MDM family is vital for normal breast development, but also for preserving genomic fidelity. The MDM family members are best characterized for their negative regulation of the major tumour suppressor p53 to modulate stress responses. Their impact on other cellular regulators is emerging. Inappropriately elevated protein levels of the MDM family are highly associated with an increased risk of cancer incidence. Exploration of the MDM family members as cancer therapeutic targets is relevant for designing tailored anti-cancer treatments, but successful approaches must strategically consider the impact on both the target cancer and adjacent healthy cells and tissues. This review focuses on recent findings pertaining to the role of the MDM family in normal and malignant breast cells.
- Julia P. Cooper (Telomere Biology Center for Cancer Research Bethesda USA),
- Daniel Durocher (DNA Damage The Lunenfeld-Tanenbaum Research Institute Toronto Ontario Canada),
- Marcos Malumbres (CNIO Spain)
- Antoine van Oijen (Single-molecule biophysics, DNA replication, School of Chemistry, University of Wollongong NSW Australia).
- ‘+’ lots more
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8th Garvan Signalling Symposium
We welcome scientists at all levels, including students, post-docs, research staff and senior lab heads. The intimate nature of the meeting and enjoyable social functions promotes a collegial atmosphere and excellent networking opportunities. A poster session will be held on the Monday afternoon with generous prizes. Slots have been reserved for short (15 minutes) talks to be selected from submitted abstracts.
The meeting is held at the Garvan Institute in the glamorous Darlinghurst region of Sydney, close to the city, Oxford Street, King’s Cross and the harbour.
This years exciting program features state-of-the-art technologies to investigate a wide range of diseases including cancer, immunology, neuroscience and metabolic disorders. Special sessions focus on in vivo/intravital signalling, proteomics, control of gene regulation and the structural basis of signalling.
Click Here for more information and to register
The 16th Australian Cell Cycle Meeting: “Cell Cycle, DNA Damage Response & Telomeres” will be held from Monday the 27th to Wednesday the 29th of March, 2017 at the Powerhouse Museum, in Sydney Australia.
The 2017 meeting will be the largest ever ACCM meeting, bringing together the fields of Cell Cycle, DNA Damage Response, and Telomere biology into one amazing meeting.
We are also very excited to announce 4x Plenary Lectures for #ACCM2017:
Julia P. Cooper
Telomere Biology Center for Cancer Research (NCI) Bethesda, MD, USA
DNA Damage The Lunenfeld-Tanenbaum Research Institute Toronto, Ontario Canada
Cell Division & Cancer National Cancer Research Centre (CNIO) Madrid, Spain
Antoine van Oijen
Single-molecule biophysics, DNA replication Head School of Chemistry, University of Wollongong NSW, Australia
Registration for the ACCM2017 will open in October 2016, and more details, including a fantastic line up of National speakers will be announced…
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Dr Cesare’s laboratory has postdoctoral positions, fully funded for three years, starting in late 2016 or early 2017. We are in search of exceptional young scientists, interested in pursuing research on telomeres and genome stability. Opportunities exist in my lab for post-doctoral scientists to investigate:
1) the interplay between genomic DNA replication stress, or DNA damage, and telomere deprotection
2) mechanisms of telomere deprotection during ageing and in cancer
3) telomere biology in mitosis
4) mitotic chromosome dynamics
5) post-translational modifications in telomere deprotection signalling
6) nuclear architecture in the DNA damage response
Ideal candidates will be hard working, independent, and creative in their experimental approach. I also welcome candidates with established excellence in CRISPR/Cas9 mediated gene-editing, quantitative microscopy and/or automated imaging analysis, super-resolution microscopy, proteomics, ChIP-seq and RNA-seq.
Dr Cesare’s is located at the Children’s Medical Research Institute (CMRI) in Sydney, Australia. CMRI is home to the highest concentration of telomere research labs at a…
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A defining feature in over 2/3rds of all solid tumours is the continual loss and gain of whole are small parts of chromosomes. This instability, or CIN for short, strongly implicated in tumour initiation, progression, chemoresistance and poor prognosis. CIN is created through failures during mitosis, whereby whole or parts of a chromosome are segregated incorrectly, thereby created daughter cells with unequal chromosome numbers. Consequently, understanding how mitosis is regulated is essential for uncovering the mechanisms allowing CIN to arise and drive cancer. In our recent publication, we discovered the mechanisms controlling the key regulatory pathway critical to ensuring cells exit mitosis correctly. At the centre of this pathway is a gene call MASTL (short for ‘Microtubule Associated Serine/Threonine Kinase-Like’). The primary function of MASTL is to ensure that the cellular breaks (the phosphatase PP2A), is turned off during mitosis so that the accelerator (Cdk1 kinase) can drive the cell into mitosis. Much like a car, having the accelerator and breaks on at the same time is a bad idea, unless you like the smell of burning rubber. To successfully exit mitosis, and to perfectly segregate chromosomes, the cell must take the foot off the accelerator and turn on the breaks. Because MASTL is the central regulator ensuring the breaks are coordinated with the accelerator, it is essential to understand how MASTL is controlled. To this end, we uncovered that MASTL must be rapidly turned off to allow cells to exit mitosis, and this inactivation is carried out by another cellular brake call PP1 phosphatase (Rogers et al, JCS 2016). Now that we have identified and mapped this novel mitotic exit switch, we hope to be able to shed new light on how CIN drives the initiation and evolution cancer. We believe that with further study we will be able to better predict patient response to chemotherapy, and also identify new ways to ‘switch off’ highly unstable tumours, thereby improving treatment for patients that currently have a very poor prognosis.
Image of Interphase HeLa cell stained for Actin (red), DNA (blue) and the co-localisation of MASTL and PP1 by Proximity Ligation Assay (PLA; green).
Credit: Sam Rogers and Cell Division Lab
Great news, we have a new Mini-Review published in Frontiers Oncology entitled “Clinical Overview of MDM2/X-Targeted Therapies“, which is apart of the Research Topic Human tumor-derived p53 mutants: a growing family of oncoproteins
Here is a little snippet from the Abstract to wet your appetite!
MDM2 and MDMX are the primary negative regulators of p53, which under normal conditions maintain low intracellular levels of p53 by targeting it to the proteasome for rapid degradation and inhibiting its transcriptional activity. Both MDM2 and MDMX function as powerful oncogenes and are commonly over-expressed in some cancers, including sarcoma (~20%) and breast cancer (~15%).
In this overview, we will review the current MDM2- and MDMX-targeted therapies in development, focusing particularly on compounds that have entered into early phase clinical trials. We will highlight the challenges pertaining to predictive biomarkers for and toxicities associated with these compounds, as well as identify potential combinatorial strategies to enhance its anti-cancer efficacy.
The article is Open Access, which means its free for everyone and anyone to read and download!
You can view and download it directly here [Link]
Its no secrete that Funding for Science in Australia, and around the world (see refs below), is in decline. The result is lower and lower success rates. While we wait for the #NHMRC to release the outcomes for 2015, the word on the street is that we can expect only 10-12% of grants to be successful. In other words, for 90% of Australia’s researchers they are wasting ~3 months of the year for nothing. Consequently as the funding pool decreases, funds naturally flow towards ‘sure bet’ senior researchers. This means that this wasted time is felt the hardest by early- and mid- career researchers (#EMCRs) who cannot compete with the long CVs of their senior peers, and are seen as a potential risky investment. Below is a graph I put together from the 2013 data, which is the most up to date information currently at hand. This trend of funding more senior researchers is clearly seen in the massive increase in average age of the CIA (chief investigator) on project grants over the past 30 years. It used to peak around 40 years, which perfectly aligned with the drop off in fellowships. So there was a very clear and clean transition from Post-Doctoral Funding for those that wanted to transition to a team leader role. However now, the average age has shifted to >50 years. This has created a significant 10-15 year ‘Funding Hole’ for EMCRs, where there are very limited number of fellowships on offer, and little to no chance of securing a project grant. While there has been a lot of talk about this black box, no solution or action has been taken to stem the loss of young, bright and talented researchers being forced out of research. Without action soon, we run the real risk that there will be no succession plan, and Australia’s ability to remain internationally competitive will be set back decades.