Munarriz Eliana, Bano Daniele, Sayan A Emre, Rossi Mario, Melino Gerry, Nicotera Pierluigi
Medical Research Council, Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK.
Biochem Biophys Res Commun. 2005 Aug 5;333(3):954-60. doi: 10.1016/j.bbrc.2005.05.188.
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.
p73是一种属于p53家族的转录因子，其功能受其稳态蛋白稳定性的精细调控。p73蛋白的降解/稳定可通过部分依赖于泛素蛋白酶体系统（UPS）的机制进行调控：（i）Itch/NEDD4样UPS降解，（ii）NEDD8 UPS降解，以及（iii）NQO1 20S蛋白酶体依赖性（但不依赖泛素）降解。在此，我们表明，在体外，钙蛋白酶I可在两个不同位点切割p73：第一个富含脯氨酸的区域和寡聚化结构域内。因此，不同的p73异构体可被钙蛋白酶降解，即N端异构体（TAp73和DeltaNp73）以及C端异构体（α、β、γ、δ）。此外，在培养细胞中过表达特异性内源性钙蛋白酶抑制剂钙蛋白酶抑制蛋白，可提高p73的稳态水平。这表明钙蛋白酶可能在p73蛋白稳定性的调节中发挥生理作用。
