Transactivation-dependent and -independent regulation of p73 stability.
The tumor suppressor p53 regulates its own stability by transcriptionally activating Mdm2, Pirh2, and COP1, which target p53 for degradation. However, whether such a negative feedback mechanism exists to regulate the stability of p73, the structural and functional homologue of p53, is unclear. Unlike p53, p73 is not mutated in cancers, but its expression is significantly elevated. Thus, we have investigated the regulation of p73 turnover. Our data suggest the existence of a negative feedback mechanism for p73 degradation. p73 mutants with compromised transactivation activity are generally more stable than the full-length TAp73 form. TAp73 appears to promote its own turnover as well as that of other p73 forms, including the DeltaNp73 that lacks the amino-terminal transactivation domain, in a transactivation-dependent manner. This degradation-inducing property of TAp73 was inhibited only by p73 mutants that also inhibit the transactivation activity TAp73 but not by mutant p53, highlighting the specificity in the regulation of p73 stability. Moreover, regions in the amino and carboxyl termini of p73 confer both stabilizing and destabilizing effects on the protein, independent of its transactivation ability. Finally, we have identified the regions between amino acids 56 and 248 of p73 as being the region required for p73-mediated and for ubiquitin-mediated degradation. Taken together, the data suggest that p73 turnover is tightly regulated in a transactivation-dependent and -independent manner, resulting in the controlled expression of the various p73 forms.
Dulloo
Iqbal
I
Laboratory of Molecular Carcinogenesis, Division of Cellular and Molecular Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610.
Sabapathy
Kanaga
K
D001483:Base Sequence; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D017384:Sequence Deletion; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D003513:Cycloheximide; D008156:Luciferases