Novel technology aids pharmaceutical quest against cancer
The p53 gene — the most frequently mutated gene in cancer — is a tumour suppressor whose function is to interfere with cell cycle progression and stop the onset of cancer. Apart from therapeutic relevance, p53 is also important for the protection of individuals from chemotherapeutic and radiological injury. The primary objective of the EU-funded ONCOSWITCH (In vivo analysis of the p53 and p73 tumor suppressors using a unique mouse model) project was to develop a pre-clinical model of the p53 tumour suppressor for investigating the response to anti-cancer drugs. This genetically engineered mouse model allowed the targeting of p53 function through a novel technology that reversibly interfered with p53 protein stabilisation. This was achieved by fusing p53 to a heterologous degradation sequence (degron) that is regulated by the plant hormone, auxin, or its chemical derivatives. Following extensive in vitro and in vivo validation of the auxin-induced degron (AID) regulation technology, the consortium proceeded with the in vivo mouse model of p53. They determined the minimal degron sequence that mediated efficient degradation of the protein and tagged p53-AID with a fluorescent marker, confirming that a plant hormone affected the stability of p53-AID. As an alternative strategy, scientists inserted a tetracycline response element (TRE) into the control region of the p53 gene to elicit tetracycline-dependent regulation of gene expression. They successfully generated two p53-TRE animal models. The next step would be to validate these preclinical models in various cancer types, including skin, breast and pancreas. Overall, the deliverables of the ONCOSWITCH project should prove to be an invaluable tool in the pharmaceutical industry for screening new drugs. Scientific advances over the years with regard to the development of targeted anti-cancer therapies have failed to cure many types of cancer. The ONCOSWITCH pre-clinical models are expected to open new avenues for the discovery of anti-cancer treatments.
Keywords
Cancer, p53, drug, degron, auxin, tetracycline-responsive element
