Regulation of the p73 protein stability and degradation.
p73, a homologue to the tumor suppressor gene p53, is involved in tumorigenesis, though its specific role remains unclear. The gene has two distinct promoters which allow the formation of two protein isoforms with opposite effects: full-length transactivating (TA) p73 shows pro-apoptotic effects, while the shorter DeltaNp73, which lacks the N-terminal transactivating domain, has an evident anti-apoptotic function. Unlike p53, the p73 gene is rarely mutated in human cancers. However, alterations in the relative levels of TA and DeltaNp73 have been shown to correlate with prognosis in several human cancers, suggesting that the fine regulation of these two isoforms is of pivotal importance in controlling proliferation and cell death. Much effort is currently focused on the elucidation of the mechanisms that differentially control TA and DeltaNp73 activity and protein stability, a process complicated by the finding that both proteins are regulated by a similar suite of complex post-translational modifications that include ubiquitination, sequential phosphorylation, prolyl-isomerization, recruitment into the PML-nuclear body (PML-NB), and acetylation. Here we shall consider the main regulatory partners of p73, with particular attention to the recently discovered Itch- and Nedd8-mediated degradation pathways, along with the emerging roles of PML, p38 MAP kinase, Pin1, and p300 in p73 transcriptional activation, and possible mechanisms for the differential regulation of the TAp73 and DeltaNp73 isoforms.
Oberst
Andrew
A
IDI-IRCCS Biochemistry Lab, c/o Department of Experimental Medicine, University of Rome Tor Vergata, Rome 00133, Italy.
Rossi
Mario
M
Salomoni
Paolo
P
Pandolfi
Pier Paolo
PP
Oren
Moshe
M
Melino
Gerry
G
Bernassola
Francesca
F
D017209:Apoptosis / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D004795:Enzyme Stability; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000502:physiology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C000606369:delta Np73 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2