Hernández-Monge Jesús, Rousset-Roman Adriana Berenice, Medina-Medina Ixaura, Olivares-Illana Vanesa
Instituto de Física, Universidad Autónoma de San Luis Potosí, Av Manuel Nava No 6 Zona Universitaria CP 78290. SLP, México.
Genes Cancer. 2016 Sep;7(9-10):278-287. doi: 10.18632/genesandcancer.120.
The orchestrated crosstalk between the retinoblastoma (RB) and p53 pathways contributes to preserving proper homeostasis within the cell. The deregulation of one or both pathways is a common factor in the development of most types of human cancer. The proto-oncoproteins MDMX and MDM2 are the main regulators of the well- known tumor suppressor p53 protein. Under normal conditions, MDM2 and MDMX inhibit p53, either via repression of its transcriptional activity by protein-protein interaction, or via polyubiquitination as a result of MDM2-E3 ubiquitin ligase activity, for which MDM2 needs to dimerize with MDMX. Under genotoxic stress conditions, both become positive regulators of p53. The ATM-dependent phosphorylation of MDM2 and MDMX allow them to bind mRNA, these interactions promote p53 translation. MDM2 and MDMX are also being revealed as effective regulators of the RB protein. MDM2 is able to degrade RB by two different mechanisms, that is, by ubiquitin dependent and independent pathways. MDMX enhances the ability of MDM2 to bind and degrade RB protein. However, MDMX also seems to stabilize RB through interaction and competition with MDM2. Here, we will contextualize the findings that suggest that the MDM2 and MDMX proteins have a dual function on both p53 and RB.
视网膜母细胞瘤（RB）通路与p53通路之间精心编排的相互作用有助于维持细胞内适当的稳态。一条或两条通路的失调是大多数类型人类癌症发生发展的共同因素。原癌蛋白MDMX和MDM2是著名的肿瘤抑制蛋白p53的主要调节因子。在正常情况下，MDM2和MDMX通过蛋白质-蛋白质相互作用抑制p53的转录活性，或通过MDM2-E3泛素连接酶活性导致的多聚泛素化来抑制p53，而MDM2需要与MDMX二聚化才能发挥此作用。在基因毒性应激条件下，二者都成为p53的正向调节因子。MDM2和MDMX的ATM依赖性磷酸化使其能够结合mRNA，这些相互作用促进p53的翻译。MDM2和MDMX也被发现是RB蛋白的有效调节因子。MDM2能够通过两种不同机制降解RB，即通过泛素依赖性和非依赖性途径。MDMX增强MDM2结合和降解RB蛋白的能力。然而，MDMX似乎也通过与MDM2的相互作用和竞争来稳定RB。在此，我们将阐述一些研究结果，这些结果表明MDM2和MDMX蛋白对p53和RB都具有双重功能。
