The p53-Mdm2 module and the ubiquitin system.
The p53 tumor suppressor protein is a short-lived protein, which is stabilized in response to cellular stress. The ubiquitination and degradation of p53 are largely controlled by Mdm2, an oncogenic E3 ligase. Stress signals lead to p53 stabilization either by induction of covalent modifications in Mdm2 and p53, or through altered protein-protein interactions. Mdm2 also harbors a post-ubiquitination function, probably enabling efficient targeting of ubiquitinated p53 to the proteasome. p53 ubiquitination is associated with its export from the nucleus into the cytoplasm. However, the exact site of degradation of p53 is presently under debate. p53 may be targeted by other E3 ligases besides Mdm2, as well as by non-proteasomal mechanisms. Despite extensive information about p53 degradation, many important aspects remain unresolved.
Michael
Dan
D
Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot 76100, Israel.
Oren
Moshe
M
D003546:Cysteine Endopeptidases / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D013312:Stress, Physiological / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex