McCubrey James A, Lertpiriyapong Kvin, Fitzgerald Timothy L, Martelli Alberto M, Cocco Lucio, Rakus Dariusz, Gizak Agnieszka, Libra Massimo, Cervello Melchiorre, Montalto Guiseppe, Yang Li V, Abrams Stephen L, Steelman Linda S
Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Department of Comparative Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
Adv Biol Regul. 2017 Jan;63:32-48. doi: 10.1016/j.jbior.2016.10.001. Epub 2016 Oct 6.
TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation. Radiation will induce Ataxia telangiectasia mutated (ATM) and other kinases that results in the phosphorylation and activation of TP53. TP53 is also negatively regulated by other mechanisms, such as ubiquitination by ligases such as MDM2. While TP53 has been documented to control the expression of many "classical" genes (e.g., p21, PUMA, Bax) by transcriptional mechanisms for quite some time, more recently TP53 has been shown to regulate microRNA (miR) gene expression. Different miRs can promote oncogenesis (oncomiR) whereas others act to inhibit tumor progression (tumor suppressor miRs). Targeted therapies to stabilize TP53 have been developed by various approaches, MDM2/MDM4 inhibitors have been developed to stabilize TP53 in TP53-wild type (WT) tumors. In addition, small molecules have been isolated that will reactivate certain mutant TP53s. Both of these types of inhibitors are in clinical trials. Understanding the actions of TP53 may yield novel approaches to suppress cancer, aging and other health problems.
TP53是一种关键的肿瘤抑制基因，可调节细胞周期进程、细胞凋亡、细胞衰老以及许多其他对控制正常细胞生长和死亡至关重要的特性。由于TP53对基因表达和细胞生理学具有多效性作用，该肿瘤抑制基因的突变会导致多种生理效应。TP53突变在众多癌症中经常被检测到。TP53的表达可由用于治疗癌症患者的各种药物诱导，如化疗药物和电离辐射。辐射会诱导共济失调毛细血管扩张症突变基因（ATM）和其他激酶，导致TP53磷酸化并激活。TP53也受到其他机制的负调控，如MDM2等连接酶的泛素化作用。虽然TP53通过转录机制控制许多“经典”基因（如p21、PUMA、Bax）的表达已有相当长一段时间，但最近研究表明TP53还可调节微小RNA（miR）基因的表达。不同的miR可促进肿瘤发生（致癌miR），而其他miR则可抑制肿瘤进展（肿瘤抑制miR）。通过各种方法已开发出稳定TP53的靶向疗法，MDM2/MDM4抑制剂已被开发用于在TP53野生型（WT）肿瘤中稳定TP53。此外，还分离出了能重新激活某些突变型TP53的小分子。这两类抑制剂都在进行临床试验。了解TP53的作用可能会产生抑制癌症、衰老和其他健康问题的新方法。
