The transcription factors p53 and p73 are critical to the induction of apoptotic cell death, particularly in response to cell stress that activates c-Jun N-terminal kinase (JNK). Mutations in the DNA-binding domain of p53, which are commonly seen in cancers, result in conformational changes that enable p53 to interact with and inhibit p73, thereby suppressing apoptosis. In contrast, wild-type p53 reportedly does not interact with p73. We found that JNK-mediated phosphorylation of Thr⁸¹ in the proline-rich domain (PRD) of p53 enabled wild-type p53, as well as mutant p53, to form a complex with p73. Structural algorithms predicted that phosphorylation of Thr⁸¹ exposes the DNA-binding domain in p53 to enable its binding to p73. The dimerization of wild-type p53 with p73 facilitated the expression of apoptotic target genes [such as those encoding p53–up-regulated modulator of apoptosis (PUMA) and Bcl-2-associated X protein (BAX)] and, subsequently, the induction of apoptosis in response to JNK activation by cell stress in various cells. Thus, JNK phosphorylation of mutant and wild-type p53 promotes the formation of a p53/p73 complex that determines cell fate: apoptosis in the context of wild-type p53 or cell survival in the context of the mutant. These findings refine our current understanding of both the mechanistic links between p53 and p73 and the functional role for Thr⁸¹ phosphorylation.

转录因子p53和p73对于诱导凋亡性细胞死亡至关重要，尤其是在激活c-Jun N端激酶（JNK）的细胞应激反应中。在癌症中常见的p53 DNA结合结构域突变导致构象变化，使p53与p73相互作用并抑制p73，从而抑制了细胞凋亡。相反，据报道野生型p53不与p73相互作用。我们发现JNK介导的p53富脯氨酸域（PRD）中的Thr ⁸¹磷酸化使野生型p53以及突变体p53与p73形成复合物。结构算法预测Thr ^81的磷酸化暴露p53中的DNA结合结构域以使其与p73结合。野生型p53与p73的二聚化促进了凋亡靶基因的表达（例如编码p53的凋亡调控因子（PUMA）和Bcl-2相关X蛋白（BAX）的表达），并随后诱导各种细胞中细胞应激对JNK激活作出响应的凋亡 因此，突变体和野生型p53的JNK磷酸化促进了决定细胞命运的p53 / p73复合物的形成：在野生型p53的情况下细胞凋亡或在突变体的情况下细胞存活。这些发现完善了我们目前对p53和p73之间的机械联系以及Thr ⁸¹磷酸化的功能作用的理解。