Mice With A Mutation In The Mdm2 Gene That Interferes With Mdm2/Ribosomal Protein Binding Develop Bone Marrow Failure

MDM2, an E3 ubiquitin ligase, is an important negative regulator of p53. In turn the MDM2 gene is a transcriptional target of p53, forming a negative feedback loop that is important in cell cycle control. It has recently become apparent that the ubiquitination of p53 by MDM2 can be inhibited by the binding of some ribosomal proteins, including RPL5 and RPL11, and that the resulting increase in p53 levels may be important in the red cell aplasia seen in DBA and in 5q- MDS. DBA and 5q- MDS are associated with inherited (DBA) and acquired (5q-MDS) haploinsufficiency of ribosomal proteins. A mutation in MDM2 causing a C305F amino acid substitution blocks the binding of ribosomal proteins. Mice harboring this mutation, retain a normal p53 response to DNA damage, but lack the p53 response to perturbations in ribosome biogenesis.