Drugs that more effectively target tumour cells and that have minimal toxicity for normal tissue will increase the efficacy of anti-cancer treatment.
Current Laboratory Members
Associate Professor Brian Gabrielli: Dr Won Lee, Dr Rose Boutros, Dr Sandra Pavey, Mrs Nichole Giles, Mr Kee Ming Chia, Mr Matthew Wigan, Ms Tanya Pike, Ms Robyn Warrener, Mrs Puji Astuti, Ms Vanessa Oakes, Ms Kelly Brooks and Ms Huong Le.
The Cell Cycle Group studies the mechanisms which underpin normal cell growth and division. In cancer, these control mechanisms, checkpoints, are often defective, resulting in uncontrolled growth. A detailed understanding of the mechanism of checkpoints makes it possible to target these defective checkpoint mechanisms to specifically destroy tumour cells.
Current Research Projects
Controlling entry into mitosis
The lab focuses on the mechanisms regulating progression into mitosis. Our studies on one potential regulator, the G2 phase cyclin dependent kinase cyclin A/cdk2, have demonstrated that it controls the timing of activation of cyclin B/cdk1 which is critical for mitosis. Surprisingly, cyclin A/cdk2 appears to control the timing of this activation differently in different locations within the cells, in the nucleus, cytoplasm and centrosome. We have also identified APC, a tumour suppressor gene product, as a substrate for cyclin A/cdk2. Phosphorylation by cyclin A/cdk2 is required for correct mitotic spindle orientation. This provides an unexpected link between normal cell cycle control and uncontrolled cell division, and metastasis in cancer. We are also examining the mechanism by which cyclin A/cdk2 regulates the timing of cyclin B/cdk1 activation and mitotic entry.
Figure 1: Cell cycle progression is controlled by the ordered activation of cyclin /cdks, and can be inhibited by inhibitory subunits such as p16 and p21 proteins. Checkpoints block progression at specific points in the cell cycle in response to specific stresses.
Figure 2: Live cell time lapse microscopy shows cells undergoing mitosis. Control cells rapidly form a metaphase plate and divide their DNA symmetrically. In cyclin A depleted cells, the chromosomes fail to align and the partially formed metaphase plate rotates within the cells (arrows), dramatically altering the plan of division.
Defective cell cycle responses to ultraviolet radiation in melanoma
A G2 phase cell cycle checkpoint delay is induced by physiological ultraviolet radiation of human skin, but this checkpoint response is defective in melanomas. We have found that the cell cycle response allows time for the cells to properly repair and repackage their DNA before partitioning the replicated chromosomes in mitosis. The checkpoint response also offers an opportunity to target melanomas with a defective checkpoint using new drug combinations based on our understanding the defective mechanism. Other studies have examined the molecular basis of the relationship between, ultraviolet radiation, the pigmentation gene MC1R, and the melanoma susceptibility genes B-Raf and p16. We have found that the increased p16 expression in skin following 
exposure to ultraviolet radiation is regulated by a signalling pathway involving B-Raf and that MC1R contributes in an unexpected manner to p16 expression after UV exposure.
Figure 3: Human skin either control (A) or irradiated (B) with a suberythemal dose of ultraviolet radiation were analysed for the expression of melanoma susceptibility gene product p16.
A novel signalling outcome for the MAPK pathway
The Ras-Raf-MEK-ERK signalling pathway is well studied. We have previously found that the MEK1 isoform is regulated in a unique manner in mitosis. It is proteolytically truncated in the N-terminal domain removing its ERK binding domain and nuclear localisation signal, and appears incapable of activating ERK the only known substrate of MEK. Inappropriate presence of this truncated MEK1 (tMEK) delays entry into mitosis, independent of its normal transduction partner ERK, and independent of ATM/ATR and chk1/chk2 mechanisms. We have defined the structural features of tMEK required for this arrest function, and the mechanism by which it imposes the cell cycle arrest. We are currently search for the physiological signals that utilise this mechanism to impose a transient cell cycle arrest.
Defining the tumour selectivity of novel anti-cancer drugs
We are exploring ways of exploiting defective checkpoints in cancers as an “Achilles Heel” to specifically target the destruction of tumours. Histone deacetylase inhibitors (HDACi) target a checkpoint that is defective in a wide range of tumour cell lines but intact in normal tissue. Investigations have uncovered the molecular basis of the some of the effects of these drugs. We are now trying to identifying new targets in the same defective checkpoint mechanism that may be even more clinically effective than the current generation HDACi. We are also taking a new approach called a synthetic lethality screen. This screen is to identify all genes that when depleted synergise with the HDACi to more efficiently kill tumour cells. The gene identified will then be the targets for small molecule screens to identify drugs that inhibit their activity/function and use these in a logical combination with the HDACi as a more effective, and targeted anti-cancer therapy. This synthetic lethality screen will be used in other situations such as identifying genes that when depleted specifically kill melanoma cells with a defective UV response checkpoint.
Figure 4: (A) Normal cells have intact checkpoints and respond to stress such as HDACi by arresting the cell cycle until the stress is resolved. (B) Loss of one checkpoint reduces viability in response to the stress as a second checkpoint will partly compensate for loss of the primary checkpoint. (C) Knocking out the secondary checkpoint using either small molecule inhibitors or siRNA will result in complete loss of viability with the stress.
Associate Professor Gabrielli is currently offering postgraduate projects in his laboratory. Contact him directly for more information.