Tumour Suppression

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Tumour Suppression - Research at Peter Mac

The Tumour Suppression laboratory studies the regulation and function of tumour suppressors, with the aim to manipulate these proteins to kill cancer cells.

Research Focus

Identify key determinants of regulation of the tumour suppressors p53 and the promyelocytic leukemia (PML) protein. Define the regulatory mechanisms and function of mutant forms of p53. Investigate the involvement of the E6AP-PML axis in cancer development, with a focus on prostate cancer. Identify novel pathways of cellular stress response. Explore the regulation of cellular aging and its link to tumour suppression.

Research Overview

The Tumour Suppression laboratory, established in 2008, aims to identify the key regulatory nodes in tumour suppression with the ultimate ambition of applying and translating this knowledge into the clinical setting. The most important agent of the body for fighting cancer is the cellular protein p53. It plays a key role in responding to assaults that damage DNA. Upon activation, p53 acts to eliminate cells of cancerous potential by halting their growth. In more than 50% of all human cancers, it loses its anticancer properties through mutation. In an insidious manner, mutation of p53 not only robs it of its ability to prevent cancer, but also confers it with new cancer promoting capacity. The biological outcomes of the mutant p53 ‘gain of function’ include the induction of chemoresistance, and an enhanced proliferative and metastatic potential. To better treat cancer we need to understand how both normal p53 and mutant p53 are controlled. Surprisingly, the function and regulation of mutant p53 is poorly understood. Our recent findings demonstrate that the tumour suppressor PML is a key positive regulator of mutant p53. Strikingly, we found that PML is essential for the proliferation of cancer cells bearing mutant p53, suggesting that the tumour suppression function of PML depends on the status of p53. This work has opened exciting new areas of research, and includes the potential identification of new anti-cancer targets aimed at the mutant p53 pathway. The second major area of research in our lab is based on our recent discovery revealing a novel mechanism regulating the turnover of the PML tumour suppressor. PML is an important tumour suppressor regulating multiple stress signalling pathways. The involvement of PML in cancer has been established in mouse models for cancer, and in human samples. We have recently demonstrated that E6AP is a key regulator of the PML protein. We show that E6AP acts to mediate the destruction of the PML protein. This finding has opened up many areas of research with broad and far-reaching implications for our understanding of tumour suppression by PML and identification of novel and attractive anti-cancer targets.