TP53 missense mutations significantly influence the development and progression of various human cancers via their gain of new functions (GOF) through different mechanisms. Here we report a unique mechanism underlying the GOF of p53-R249S (p53-RS), a p53 mutant frequently detected in human hepatocellular carcinoma (HCC) that is highly related to hepatitis B infection and aflatoxin B1. A CDK inhibitor blocks p53-RS’s nuclear translocation in HCC, whereas CDK4 interacts with p53-RS in the G1/S phase of the cells, phosphorylates it, and enhances its nuclear localization. This is coupled with binding of a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) to p53-RS, but not the p53 form with mutations of four serines/threonines previously shown to be crucial for PIN1 binding. As a result, p53-RS interacts with c-Myc and enhances c-Myc-dependent rDNA transcription key for ribosomal biogenesis. These results unveil a CDK4-PIN1-p53-RS-c-Myc pathway as a novel mechanism for the GOF of p53-RS in HCC.

TP53错义突变通过不同的机制获得新功能（GOF），从而显着影响各种人类癌症的发生和发展。在这里，我们报告了p53-R249S（p53-RS）GOF的潜在独特机制，p53-R249S（p53-RS）是在人类肝细胞癌（HCC）中经常检测到的p53突变体，与B型肝炎感染和黄曲霉毒素B1高度相关。CDK抑制剂在肝癌中阻断p53-RS的核易位，而CDK4在细胞的G1 / S期与p53-RS相互作用，使其磷酸化，并增强其核定位。这与肽基-脯氨酰顺反异构酶NIMA-interacting 1（PIN1）与p53-RS的结合结合在一起，但不与p53形式结合，突变的四个丝氨酸/苏氨酸对PIN1结合至关重要。因此，p53-RS与c-Myc相互作用并增强c-Myc依赖性核糖体生物发生的rDNA转录键。这些结果揭示了CDK4-PIN1-p53-RS-c-Myc途径是肝癌中p53-RS GOF的新机制。