Borini Etichetti Carla M, Arel Zalazar Evelyn, Cocordano Nabila, Girardini Javier
Instituto de Fisiología Experimental de Rosario, IFISE, CONICET-UNR, Rosario, Argentina.
Instituto de Inmunología Clínica y Experimental de Rosario, IDICER, CONICET-UNR, Rosario, Argentina.
Front Oncol. 2020 Nov 5;10:595034. doi: 10.3389/fonc.2020.595034. eCollection 2020.
Missense mutations in the gene are among the most frequent alterations in human cancer. Consequently, many tumors show high expression of p53 point mutants, which may acquire novel activities that contribute to develop aggressive tumors. An unexpected aspect of mutant p53 function was uncovered by showing that some mutants can increase the malignant phenotype of tumor cells through alteration of the mevalonate pathway. Among metabolites generated through this pathway, isoprenoids are of particular interest, since they participate in a complex process of posttranslational modification known as prenylation. Recent evidence proposes that mutant p53 also enhances this process through transcriptional activation of , the gene encoding the methyl transferase responsible for the last step of protein prenylation. In this way, mutant p53 may act at different levels to promote prenylation of key proteins in tumorigenesis, including several members of the RAS and RHO families. Instead, wild type p53 acts in the opposite way, downregulating mevalonate pathway genes and . This oncogenic circuit also allows to establish potential connections with other metabolic pathways. The demand of acetyl-CoA for the mevalonate pathway may pose limitations in cell metabolism. Likewise, the dependence on S-adenosyl methionine for carboxymethylation, may expose cells to methionine stress. The involvement of protein prenylation in tumor progression offers a novel perspective to understand the antitumoral effects of mevalonate pathway inhibitors, such as statins, and to explore novel therapeutic strategies.
该基因中的错义突变是人类癌症中最常见的改变之一。因此，许多肿瘤显示出p53点突变体的高表达，这些突变体可能获得有助于发展侵袭性肿瘤的新活性。通过表明一些突变体可以通过改变甲羟戊酸途径来增加肿瘤细胞的恶性表型，发现了突变型p53功能的一个意外方面。在通过该途径产生的代谢物中，类异戊二烯特别受关注，因为它们参与了一个称为异戊二烯化的复杂的翻译后修饰过程。最近的证据表明，突变型p53还通过转录激活负责蛋白质异戊二烯化最后一步的甲基转移酶的基因来增强这一过程。通过这种方式，突变型p53可能在不同水平上发挥作用，促进肿瘤发生中关键蛋白质的异戊二烯化，包括RAS和RHO家族的几个成员。相反，野生型p53则以相反的方式起作用，下调甲羟戊酸途径基因和。这种致癌回路也允许与其他代谢途径建立潜在的联系。甲羟戊酸途径对乙酰辅酶A的需求可能会对细胞代谢造成限制。同样，羧甲基化对S-腺苷甲硫氨酸的依赖可能使细胞面临甲硫氨酸应激。蛋白质异戊二烯化参与肿瘤进展为理解甲羟戊酸途径抑制剂（如他汀类药物）的抗肿瘤作用和探索新的治疗策略提供了一个新的视角。
