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Characterize the role of Treacle (TCOF1) in AKT-regulated ribosome biogenesis


Project Description

Ribosomes are essential for cell growth and proliferation, and their biogenesis requires exquisite regulation. Aberrant ribosome biogenesis underlies diseases of ribosomes, the so-called “ribosomopathies”, and recently it has become evident that deregulated ribosome biogenesis is a characteristic of transformed cells that can be specifically targeted to treat cancer.

We have demonstrated that the kinase AKT mediates RNA Polymerase I (Pol I)-driven ribosomal RNA gene (rDNA) transcription and cooperates with MYC to achieve maximal activation of rDNA transcription, ribosome biogenesis and cell growth. Furthermore, we have identified the nucleolar protein Treacle (TCOF1) is present in the Pol I complex and is a direct AKT substrate. We hypothesized that AKT drives rDNA transcription and ribosome biogenesis through Treacle.

In order to establish phosphorylation of Treacle as a possible mechanism by which AKT regulates rDNA transcription, phosphoproteomics, immunoprecipitation, site-directed mutagenesis, real-time PCR, immunoblotting, immunofluorescence techniques will be utilized to uncover a key regulatory role of Treacle in AKT-driven ribosome biogenesis.


Researchers in the Pearson laboratory investigate the molecular basis of the regulation of signalling pathways and their control of cell growth, to understand how deregulation of this process contributes to cancer and how it can be targeted to treat the disease. We aim to understand how deregulation of this process contributes to cancer and how it can be targeted to treat the disease, by:
1) Understanding the signal transduction pathways underpinning cell growth control.
2) Conducting biochemical and cell biology analysis of the role of deregulated cell growth in cancer.
3) Analysing novel therapies targeting cell growth to treat cancer in pre-clinical models of lymphoma, ovarian and prostate cancers.
4) Pharmacogenomic analysis of the pathogenesis of ovarian cancer and predictors of response to emerging targeted therapies.
https://www.petermac.org/research/labs/rick-pearson

Peter MacCallum Cancer Centre, Melbourne Australia
Peter MacCallum Cancer Centre is Australia’s only public hospital solely dedicated to cancer, and home to the largest cancer research group in Australia. Cancer is a complex set of diseases, and modern cancer research institutes such as Peter Mac conduct research covering a diversity of topics that range from laboratory-based studies into the fundamental mechanisms of cell growth, translational studies that seek more accurate cancer diagnosis, clinical trials with novel treatments, and research aimed to improve supportive care.

All students engaged in postgraduate studies at Peter Mac are enrolled in the Comprehensive Cancer PhD (CCPhD) program, regardless of which university they are enrolled through. The program is managed by the Sir Peter MacCallum Department of Oncology (The University of Melbourne), based at Peter Mac.

Tapping into the depth and breadth of knowledge and experience offered by the ten partners of the Victorian Comprehensive Cancer Centre (VCCC) alliance, the University of Melbourne’s Comprehensive Cancer PhD Program provides a unique opportunity for multidisciplinary cancer-related PhD candidates to experience clinical and research activities across the alliance.

The Comprehensive Cancer PhD program builds on established conventional training for cancer research students providing a coordinated program of skills, research and career training in addition to usual PhD activities. The program is designed to complement existing PhD activities and provides opportunities to develop professional skills that will help candidates to fulfil their career ambitions.
https://www.petermac.org/education/comprehensive-cancer-phd-program

Funding Notes

All PhD students at Peter Mac must have a scholarship from The University of Melbourne or through another government, trust or philanthropic organisation. Before applying for a scholarship, you must have agreed on a project with an institute supervisor.

For further information about the university application process, see:
View Website

For further information regarding scholarships (both local and international), see:
View Website
Closing dates for applications for scholarships to commence in 2019: Round 1 -31 October 2018; Round 2 - 28 Nov 2018; Round 3 - 20 Feb 2019.

References

1. Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474(7353):609-615.
2. Bywater MJ, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell. 2012; 22(1):51-65.
3. Devlin JR, et al. Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. Cancer Discov. 2016.
4. Hein et al., Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. Blood (2017) [Epub ahead of print]
5. Quin J, et al. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. Oncotarget. 2016.

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