Fig. 2

A simplified scheme of p53 regulation in cells upon stress and the drugs currently evaluated in clinical trials for p53 reactivation for improved therapy in MDS and AML. In normal cells, p53 protein is activated by numerous stress conditions like, oncogene activation, telomere shortening, replication stress, DNA damage, or elevated levels of reactive oxygen species (ROS). Wild-type p53 is released from MDM2 and MDM4 by phosphorylation by ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3-related protein (ATR). (ATM-mediated phosphorylation of c-Abl mediates the release of p73 from the complex with MDM2, not shown). Consequent p53 acetylation and protein accumulation allow activation of p53 (and p73) transcriptional function. Activated ARF binds directly to MDM2 upon oncogenic stress and shifts the conformation so that p53 is released from the complex and becomes activated. ROS-activated c-Jun N-terminal kinase (JNK) was also shown to phosphorylate and activate p53 and p73. In normal cells, the negative feedback loop between p53-MDM2 is responsible for p53 protein turnover. In cancer cells amplified MDM2 prevents p53 accumulation and activation. Mutant p53 protein accumulates in large quantities in cancer cells and escapes the regulation by the p53-MDM2 feedback loop. Drugs targeting wild-type and mutant p53 appraised in clinical studies for MDS and AML are marked in bold. Modified from [63, 70, 74,75,76,77,78]. →  →  → tandem of arrows indicates a multi-step process. Created with BioRender.com