Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Sci Signal. 2018 Apr 3;11(524):eaao4170. doi: 10.1126/scisignal.aao4170.
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 Thr 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 Thr 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 Thr phosphorylation.
转录因子 p53 和 p73 对于诱导细胞凋亡至关重要，尤其是在细胞应激激活 c-Jun N 端激酶 (JNK) 时。p53 的 DNA 结合域中的突变在癌症中很常见，导致构象变化，使 p53 能够与 p73 相互作用并抑制 p73，从而抑制细胞凋亡。相比之下，野生型 p53 据报道不会与 p73 相互作用。我们发现，JNK 介导的 p53 脯氨酸丰富结构域 (PRD) 中 Thr 的磷酸化使野生型 p53 以及突变型 p53 能够与 p73 形成复合物。结构算法预测，Thr 的磷酸化使 p53 的 DNA 结合域暴露出来，从而使其能够与 p73 结合。野生型 p53 与 p73 的二聚化促进了凋亡靶基因的表达[如编码 p53 上调凋亡调节剂 (PUMA) 和 Bcl-2 相关 X 蛋白 (BAX)]，随后在各种细胞中通过细胞应激激活 JNK 诱导细胞凋亡。因此，JNK 对突变型和野生型 p53 的磷酸化促进了 p53/p73 复合物的形成，决定了细胞命运：在野生型 p53 的情况下为细胞凋亡，在突变型 p53 的情况下为细胞存活。这些发现完善了我们目前对 p53 和 p73 之间的机制联系以及 Thr 磷酸化的功能作用的理解。
