Two recent studies, one in Molecular Cell and the other in the Journal of Experimental Medicine, have shed new light on the molecular mechanisms that regulate the function and stability of p73 — a close relative of the tumour suppressor p53.

In the first study, Giannino Del Sal and colleagues investigated whether the prolyl isomerase Pin1, which is involved in regulating the apoptotic function of p53, has a similar effect on p73 function. This turned out to be the case, as Pin1 strongly enhanced p73-dependent apoptosis in p53-null cells. This effect correlated with the Pin1-dependent induction of pro-apoptotic p73 target genes, including PUMA and p53AIP1.

Pin1 recognizes phosphorylated serine or threonine residues followed by proline (pSer/pThr-Pro; where p denotes phosphorylation), and Pin1 binding induces a conformational change in its substrate. Mutational analysis of Ser/Thr-Pro sites in p73 identified three residues in the carboxyl terminus that, when mutated, decreased the Pin1-binding ability and the transcriptional activity of p73. The authors showed a Pin1-dependent conformational change in p73 in vitro, and found that Pin1-modified p73 has an increased affinity for the acetyl transferase p300. The Pin1-induced conformational change caused the p300-mediated acetylation of p73, which, in turn, promoted the transcriptional activation of p73 gene targets.

Pin1 binding to p73 also increased the half-life of p73, and the absence of Pin1 destabilized its substrate, both in normal and genotoxic-stress conditions. p73 is activated and stabilized in response to genotoxic stress by the Abl tyrosine kinase, through the p38 mitogen-activated protein kinase (MAPK) pathway. Del Sal and co-workers showed that the overexpression of Abl or p38 increased Pin1–p73 binding in response to genotoxic stress. And, importantly, the Abl-mediated stabilization of p73 and the activation of its apoptotic function were dependent on the presence of Pin1. So, the Del Sal group concluded that Pin1 is essential for the activation of the apoptotic response by p73, and that, given its role in the functioning of p53, Pin1 might be a common regulator of the p53 family.

Pier Paolo Pandolfi and co-workers also studied p73 stability, although from a different angle. The degradation of p53 is regulated by the ubiquitin–proteasome pathway, and the Pandolfi group showed that the same pathway is responsible for p73 degradation. They then made an interesting observation — the overexpression of the tumour suppressor promyelocytic leukaemia (PML) caused the dose-dependent accumulation of p73, which coincided with reduced levels of ubiquitylated p73.

So, PML seems to protect p73 from ubiquitylation, but how? PML is known to promote the acetylation of p53 by CBP (CREB-binding protein), and Pandolfi and colleagues showed that PML has a similar effect on p73 — it causes the p300-mediated acetylation and stabilization of p73. The authors suggest that the competition between acetylation and ubiquitylation might be responsible for regulating the steady-state levels of p73, which represents a new mechanism for the regulation of protein stability.

Given the involvement of PML in the pathogenesis of acute promyelocytic leukemia (APL), p73 might also be implicated in this disease. The authors hypothesize that the stability and activity of p73 might be compromised in APL. Finally, the findings of these studies make one wonder how p63 stability and function are regulated...