MDM2 and MDMX ( also known as MDM4 and HDM4/ HDMX ) downregulate the tumor suppressor p53 . In response to cellular stress , the transcription factor p53 mediates the expression of genes involved in protective processes such as DNA repair , cell cycle arrest , and apoptosis . [ 343,344 ] Binding of MDM2 and MDMX to the N - terminal transactivation domain of p53 blocks this so - called " guardian of the genome " , either by mediating its ubiquitylation that finally leads to its degradation by the proteasome [ 345 ] or by acting as a direct antagonist . [ 346 ] An upregulation of MDM2 and MDMX has been detected in many types of cancers , thus resulting in the interaction between these proteins and p53 being prime targets for anticancer strategies . Crystal structures of the complex between MDM2 and the transactivation domain of p53 reveal an a - helical conformation of the p53 interaction domain when bound to MDM2 ( Figure 16 a ) . [ 347 ] P53 hot - spot residues involve Phe19 , Trp23 , and Leu26 . [ 347 ] This structural information together with the crystallographic data of the similarly arranged p53 - MDMX complex [ 348 ] have been used as the starting point for a rational design of the corresponding PPI inhibitors . For some peptidomimetics , helical peptides derived from phage - display selections served as alternative starting points . Examples include the phagedisplay - derived peptides pDi [ 349 ] and PMI [ 350 ] that exhibit dual inhibitory effects for both the p53 - MDM2 and p53 - MDMX complexes . This is considered a desirable feature for efficient anticancer activity . Additionally , mirror - image phage - display ( MIPD ) techniques together with native chemical ligation have provided proteolytically more - resistant d - peptide inhibitors of the p53 - MDM2 interaction . However , these peptides do not feature sufficient cell permeability . [ 351][352][353 ] Finally , although mRNA display has enabled the screening of larger libraries of peptides , [ 354 ] the proteolytic instability and/or poor cellular uptake of these peptides remain major limitations of these approaches .