Interaction of the co-activator CBP/p 300 with the oncoprotein MDM2 and the tumor suppressor p53

Cell division is regulated by mutual control of activating and inhibiting proteins. Loss of this control, e.g. by acquired or inherited genetic defects, is directly linked to the formation of cancer. p53 is a specific transcription factor that responses upon genetic defects either by activation of repair mechanisms or - if the defect is irreparable - by initiation of apoptosis. Thus p53 is a key regulator in the suppression of tumor formation. To enable a normal cell divison MDM2 (a proto-oncoprotein) together with p53 interacts with CBP (CREB binding protein) and in this context p53 is labeled for degradation. This interaction is regulated by small modifications of the protein changing its structure. Tumor cells lost this and other regulatory mechanisms. This project aims at the analysis of the p53-MDM2-CBP protein complex in vitro. The proteins will be synthesized in bacteria, purified and analysed by nuclear magnetic resonance spectroscopy. Other spectroscopic methods, like measurement of circular dichroism and of fluorescence will also be used. These enables very sensitive analyses with relatively small amount of samples. In order to avoid the formation of tumors in an early stage and to develop specific therapies it is indispensable to analyse and to understand the underlying molecular mechnisms.