Pant Vinod, Larsson Connie A, Aryal Neeraj, Xiong Shunbin, You M James, Quintas-Cardama Alfonso, Lozano Guillermina
Department of Genetics, M.D. Anderson Cancer Center, Houston, Texas, 77030, USA.
Department of Hematopathology, M.D. Anderson Cancer Center, Houston, Texas, 77030, USA.
Oncotarget. 2017 Apr 18;8(16):25837-25847. doi: 10.18632/oncotarget.15552.
Disruption of the p53 tumor suppressor pathway is a primary cause of tumorigenesis. In addition to mutation of the p53 gene itself, overexpression of major negative regulators of p53, MDM2 and MDM4, also act as drivers for tumor development. Recent studies suggest that expression of splice variants of Mdm2 and Mdm4 may be similarly involved in tumor development. In particular, multiple studies show that expression of a splice variant of MDM4, MDM4-S correlates with tumor aggressiveness and can be used as a prognostic marker in different tumor types. However, in the absence of prospective studies, it is not clear whether expression of MDM4-S in itself is oncogenic or is simply an outcome of tumorigenesis. Here we have examined the role of Mdm4-S in tumor development in a transgenic mouse model. Our results suggest that splicing of Mdm4 does not promote tumor development and does not cooperate with other oncogenic insults to alter tumor latency or aggressiveness. We conclude that Mdm4-S overexpression is a consequence of splicing defects in tumor cells rather than a cause of tumor evolution.
p53肿瘤抑制通路的破坏是肿瘤发生的主要原因。除了p53基因本身的突变外，p53的主要负调控因子MDM2和MDM4的过表达也可驱动肿瘤发展。最近的研究表明，Mdm2和Mdm4剪接变体的表达可能同样参与肿瘤发展。特别是，多项研究表明，MDM4的一种剪接变体MDM4-S的表达与肿瘤侵袭性相关，可作为不同肿瘤类型的预后标志物。然而，在缺乏前瞻性研究的情况下，尚不清楚MDM4-S本身的表达是否具有致癌性，还是仅仅是肿瘤发生的结果。在这里，我们在转基因小鼠模型中研究了Mdm4-S在肿瘤发展中的作用。我们的结果表明，Mdm4的剪接不会促进肿瘤发展，也不会与其他致癌损伤协同作用来改变肿瘤潜伏期或侵袭性。我们得出结论，Mdm4-S的过表达是肿瘤细胞剪接缺陷的结果，而不是肿瘤进化的原因。
