Control of the interaction of the coactivator proteins CBP/ p300 with the tumor suppressor protein p53

Cancer is caused by damage of the genome and/or hereditary genetic defects, whereby incorrect proteins emerge in the cell. Defects on two classes of genes play a major role, on tumor suppressor genes and on oncogenes. Proteins encoded by the former inhibit cell division, whereas oncoproteins activated cell division. In a healthy organism both of them are regulated by each other and a normal cell replacement occurs. Incorrect proteins are out of control, an activation of oncoproteins or an inhibition of tumorsuppressor proteins cause an increased cell division. To target tumor cells with specific drugs, it is absolutely necessary, to know these molecular mechanisms. Communication within cells occurs by binding of molecules to proteins, whereby they are altered in their structure and their function and save or transduce a signal. The investigation of these signals of oncoproteins and tumorsuppressors is the basic of modern cancer research. This project aims to the investigation of the control of the tumorsuppressor p53 by CREB binding protein (CBP) and the oncoprotein MDM2. p53 is modified in the cell by phosphoric acid and/or acetic acid residues, binds to CBP and functions as an inhibitor of cell division. The oncoprotein MDM2, the antagonist, interferes in this interaction and forces another form of binding that triggers the degradation of the tumor-suppressor. Aim of the study is the analysis of the change in structure and binding properties of p53 by phosphorylation and acetylation using nuclear magnetic resonance spectroscopy, isothermal titration calorimetry and optical methods with the goal to understand how the activity and stability of this protein is regulated in the cell. You can also get information about general regulatory mechanism of cellular communication, which are the most important targets in anti-cancer therapy.