TY  - GEN
N2  - p53 is among the most thoroughly studied proteins to date. Its tumour suppressor activity and the consideration that inactivation of the p53 pathway is a common, if not universal, feature of all human cancers, have gained it the interest of a multitude of researches seeking new therapies against this disease. As a consequence, p53 is at the centre of a feverish research and nowadays is reported to be involved in most cellular processes. Despite the vast amount of data published, much is yet to be unravelled about the mechanisms regulating the p53 signalling network. Indeed, the p53 network is extremely intricate and complex, and from a system biology point of view it can be seen as a series of interconnected negative and positive feedback loops, which can give rise to complex dynamics such as oscillations. In the combined effort to understand more of the biological meaning of these oscillations and to study the properties of this network motif from an engineering perspective, a synthetic p53 network has been built in budding yeast with the aim of studying the network in isolation while being embedded in living cells. p53 and most proteins in the network are absent from the budding yeast genome. This diminishes the likelihood of interferences on the engineered module from the cellular environment. Surprisingly, despite the evolutionary conservation of the ubiquitin pathway from yeast to humans, p53 ubiquitylation by the E3 ubiquitin ligase Mdm2 - an event central to the oscillatory dynamics of the system - does not appear to take place in budding yeast, even when the human E2 enzyme UbcH5B is exogenously expressed. p53 is instead sumoylated by Mdm2 and sumoylation dictates the co-localization of p53 and Mdm2 to a nuclear body reminiscent of human PML bodies. In conclusion, attempting to rebuild from scratch a simplified version of the intricate p53 network, isolating it from its natural context, has proven to be a very powerful means leading to unexpected findings, testifying the usefulness of the synthetic biology approach.
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/7343/
A1  - Di Ventura, Barbara
KW  - cell biology 
KW  -  p53 
KW  -  mdm2 
KW  -  synthetic network
ID  - heidok7343
Y1  - 2006///
TI  - Engineering a synthetic p53-Mdm2 network in budding yeast
AV  - public
ER  -