 We showed that two members of the ASPP family of proteins, ASPP1 and ASPP2, specifically stimulate the apoptotic function of p53 while a third member of the ASPP family, iASPP specifically inhibits the apoptotic function of p53. Importantly, iASPP is the most conserved member of the ASPP family and the C. elegans iASPP is capable of substituting for human iASPP in all of the assays performed in human cells. ASPP1 and ASPP2 are also common activators of p53 family members. Co-expression of ASPP1 and ASPP2 stimulates the transactivation and apoptotic function of p63 and p73. Detailed analysis of ASPP2 deficient mouse demonstrated that ASPP2 is a novel haploinsufficient tumour suppressor. Deficiency of p53 and ASPP2 results in synthetic lethal suggesting ASPP2 and p53 interacts genetically. Furthermore, ASPP2 co-operates with p53 to suppress tumour growth in vivo explaining why all ASPP2 contact residues of p53 were mutated in human cancer with a relatively high frequency. In addition, we have also identified the proline rich region of p53 as the second binding site of the ASPP family, iASPP in particular. The ability of ASPP family members to selectively regulate the activity of p53Pro72 versus p53Arg72. The ASPP family of proteins present a new molecular target that might lead to the identification of novel therapeutic strategies to kill cancer cells effectively. |
