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Manipulating tumour suppression: a key to improve cancer treatment

Final Report Summary - ACTIVEP53 (Manipulating tumor suppression: a key to improve cancer treatment)

Prevention of the development of human cancer depends on a network of defence mechanisms that helps cells respond to various stress conditions. A key player in this network is the p53 tumour-suppressor protein. By inhibiting growth, p53 eliminates cancer cells and therefore prevents the development of human tumours. The functions of p53 often affect how well anti-cancer therapies work. In other words, although p53 is frequently mutated in about 50 % of all human cancers, it can also remain unchanged and could, in principle, be used to prevent tumour development. This situation is common in a wide-range of cancers, most notably breast cancer.

However, the activity of p53 is hampered by the malfunction of its many modulators, such as Mdm2 or p73. These modulators control the tumour-suppressor activity of p53 by acting upstream and/or downstream of p53. There is an urgent need to understand how the p53 modulators contribute to human tumours.

The basic idea behind the ACTIVEP53 consortium was to bring together all the leading scientists across Europe working on the p53 family, together with private companies, into one research network made up of 19 research centres and small and medium-sized enterprises (SMEs). The aim was to investigate molecular mechanisms and translate these mechanisms into a new generation of small molecules which can then be used in the treatment of patients. No consortium of this specific nature had existed before in Europe.

A list of their main achievements includes:
1. gaining insight into the mechanism ASPP2-mediated tumour suppression;
defining Hect H9 as a potential regulator of cyclin G protein levels;
2. defining Pin1 as a regulator of the mitochondrial apoptotic activity of p53;
3. showing that HIPK2 is a critical determinant of the cellular response to p53 small molecule activators, RITA and Nutlin-3. HIPK2 interacts with histones H2A and H2B.
generating yeast strains expressing lexA-p53 family member isoforms; a panel of anti-p53 and p73 intrabodies was isolated and fully characterised.
4. defining the frequency of ATM aberrations with relation to BRCA1/2 status in breast cancer, and analysing MDC1 in breast, lung and testes tumours;
5. defining the spatio-temporal behaviour of components of the DDR (53BP1, BRCA1);
6. analysing senescence markers compared to deoxyribonucleic acid (DNA) damage activation markers in human germ cells and testicular cancer;
7. defining the physiological conditions for the regulation of Strap by Mdm2;
8. validating the importance of the Lats2-p53 axis in regulation of p53 function and in prevention of human cancer;
9. showing that p53 can regulate miRNA expression with important clinical implications.

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