Okoro Danielle R, Rosso Melissa, Bargonetti Jill
The City University of New York at Hunter College and the Graduate Center, New York, NY, USA.
Genes Cancer. 2012 Mar;3(3-4):311-9. doi: 10.1177/1947601912455323.
Cancer cells often have high expression of Mdm2. However, in many cancers mdm2 is alternatively spliced, with more than 40 mRNA variants identified. Many of the alternative spliced mdm2 mRNAs have the potential to encode truncated Mdm2 isoforms. These putative Mdm2 isoforms can theoretically increase the diversity of the cancer proteome. The 3 best characterized are Mdm2-A, Mdm2-B, and Mdm2-C. As described in this review, the exogenous expression of these isoforms results in paradoxical phenotypes of transformation-associated growth as well as the inhibition of growth. Interestingly, these Mdm2 isoforms contribute tumor-promoting capacity in p53-null backgrounds. Herein we describe how alternative splicing of mdm2 may result in Mdm2 protein products that alter signal transduction to promote tumorigenesis. The tumor promoting capacity of Mdm2 isoforms is discussed in the context of functions that do not require the inhibition of p53. When N-terminal portions of Mdm2 are missing, the biochemical functions encoded by exon 12 are proposed to become more important. This may result in growth promoting functions when wild-type p53 is absent or compromised. The p53-independent tumor promoting activity of Mdm2 is proposed to result from C-terminal biochemical contributions of DNA binding, RNA binding, nucleolar localization, and nucleotide binding.
癌细胞通常具有较高的Mdm2表达。然而，在许多癌症中，mdm2会发生可变剪接，已鉴定出40多种mRNA变体。许多可变剪接的mdm2 mRNA有可能编码截短的Mdm2亚型。这些假定的Mdm2亚型理论上可以增加癌症蛋白质组的多样性。其中研究最充分的3种是Mdm2-A、Mdm2-B和Mdm2-C。如本综述所述，这些亚型的外源性表达会导致与转化相关的生长以及生长抑制等矛盾的表型。有趣的是，这些Mdm2亚型在p53缺失的背景下具有促进肿瘤的能力。在此我们描述mdm2的可变剪接如何可能导致Mdm2蛋白产物改变信号转导以促进肿瘤发生。在不需要抑制p53的功能背景下讨论了Mdm2亚型的促肿瘤能力。当Mdm2的N端部分缺失时，外显子12编码的生化功能被认为变得更加重要。当野生型p53缺失或受损时，这可能导致生长促进功能。Mdm2不依赖p53的促肿瘤活性被认为是由DNA结合、RNA结合、核仁定位和核苷酸结合的C端生化作用导致的。
