My team studied the changes in subcellular localisation and dynamics of movement of BRCA1 (a key breast cancer gene and protein) and associated partners at DNA repair sites in the nucleus of cells. The diagram at right summarizes several years work by my team and that of other labs.
My team studied the changes in subcellular transport and localisation of APC and how it is altered by cancer mutations. This had major implications for its various functions. We applied a similar approach over the last 15 years to many other proteins (including beta-catenin, axin, BARD1, BRCA1) important for the progression of colon and breast cancer.
In 1997 I returned to Sydney (after 5 years in Switzerland and the UK) and established a new lab and team at Westmead Institute for Cancer Research. The first critical step was to set up a functional assay to identify nuclear export sequences in proteins. The assay was very successful and over the years was given away freely to >100 labs around the world, helping to define the transport pathways of dozens of proteins in cells. My team used this assay to identify new regulatory pathways for BRCA1 protein in breast cancer and APC in colon cancer.
My second post-doc overseas was with Dr. Jon Karn (and Mike Gait) at the MRC Laboratory of Molecular Biology in Cambridge (England). Rev is a regulator of HIV-1 viral replication and was thought to export viral pre-mRNA out of the nucleus. However the mechanism of its nuclear transport was undefined. I showed that Rev binds the transport receptor importin-beta and that its import was dependent on Ran-GTP but blocked by binding to RNA, suggesting Rev had to be released from RNA in order to re-enter the nucleus. My work in Cambridge kick-started my subsequent independent research into nuclear transport in cells.
My first post-doc overseas was with Dr. Lukas Kuehn at the Swiss Institute for Experimental Cancer Research in Lausanne. I had become very interested in RNA-protein interactions during my PhD and this provided an amazing opportunity to extend my skills. Lukas and the team were wonderful and my work helped to show that IRPs -1 and -2 bind specific but overlapping sets of mRNAs. This was important as the IRPs control iron homeostasis in the body.