Mutant and wild-type p53 form complexes with p73 upon phosphorylation by the kinase JNK

Abstract

<p class="first" id="P3">Mutant p53 and p73 have been shown to form a complex, which renders p73 inactive, but it has been previously reported that wild-type p53 does not interact with p73. Mutations in the DNA binding domain of p53 result in structural changes that are permissive for interaction with p73. In a mouse model, p73 and p53 are important to effectively induce apoptosis, and there are several specific domains of p53 that are important for its apoptotic activity including the Proline Rich Domain (PRD). Within this domain, phosphorylation of threonine 81 (Thr ⁸¹) mediated by c-Jun N-terminal kinase (JNK) is important for apoptosis. We examined if phosphorylation of Thr ⁸¹ was important for mutant or wild-type p53 to bind to p73. Our data shows that phosphorylation of Thr ⁸¹ results in both mutant and wild-type p53 complex formation with p73. Structurally, the phosphorylation of Thr ⁸¹ exposes the DNA binding domain of which is important for binding to p73. The dimerization of p53 and p73 is important for the induction of apoptotic targets such as p53 upregulated modulator of apoptosis (PUMA) and Bcl-2-associated X protein (Bax), and the induction of apoptosis in response to JNK activation. We describe how JNK phosphorylation of mutant and wild-type p53 promotes a p53/p73 complex that dictates cell fate. These findings refine the current understanding of the role of p53 and p73 and reveal a new functional role for Thr ⁸¹ phosphorylation. </p><p id="P4">JNK phosphorylation of mutant or wild type p53 increases the interaction of p73 with mutant p53, as well as p73 and wild-type p53, leading to the induction of apoptosis (WT p53). </p>