Calpain cleavage regulates the protein stability of p73.
The function of p73, a transcription factor belonging to the p53 family, is finely regulated by its steady-state protein stability. p73 protein degradation/stabilization can be regulated by mechanisms in part dependent on the ubiquitin proteasome system (UPS): (i) Itch/NEDD4-like UPS degradation, (ii) NEDD8 UPS degradation, and (iii) NQO1 20S proteasome-dependent (but ubiquitin-independent) breakdown. Here, we show that, in vitro, Calpain I can cleave p73 at two distinct sites: the first proline-rich region and within the oligomerization domain. Consequently, different p73 isoforms can be degraded by calpains, i.e., both N-terminal isoforms (TAp73 and DeltaNp73) as well as the C-terminal isoforms (alpha, beta, gamma, delta). Moreover, overexpression of the specific endogenous calpain inhibitor, calpastatin, in cultured cells increased the steady-state p73 level. This suggests that calpains may play a physiological role in the regulation of p73 protein stability.
Munarriz
Eliana
E
Medical Research Council, Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK.
Bano
Daniele
D
Sayan
A Emre
AE
Rossi
Mario
M
Melino
Gerry
G
Nicotera
Pierluigi
P
D001483:Base Sequence; D002154:Calpain / Q000737:chemistry / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D016147:Genes, Tumor Suppressor; D006801:Humans; D006868:Hydrolysis; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids; D020033:Protein Isoforms / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D002154:Calpain