Herrero Ana B, Rojas Elizabeta A, Misiewicz-Krzeminska Irena, Krzeminski Patryk, Gutiérrez Norma C
Cancer Research Center-IBMCC (USAL-CSIC), 37007 Salamanca, Spain.
Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain.
Int J Mol Sci. 2016 Nov 30;17(12):2003. doi: 10.3390/ijms17122003.
The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation. Translational implications for MM and cancer prognosis and treatment are also reviewed.
在大多数人类癌症中，p53信号通路是失活的。尽管这种紊乱常常是通过p53自身的突变或缺失发生的，但还有其他机制可使该信号通路减弱并促进肿瘤发生。例如，重要的p53负调控因子如小鼠双微体2（MDM2）或小鼠双微体4（MDM4）的过表达、表观遗传失调，甚至mRNA剪接改变。在这项工作中，我们将综述癌症中p53信号通路抑制的不同机制，特别关注多发性骨髓瘤（MM），这是第二常见的血液系统恶性肿瘤，p53突变/缺失发生率低，但有越来越多证据表明存在间接的p53信号通路失调。还将综述MM以及癌症预后和治疗方面的转化意义。
