Coordinately regulated alternative splicing in DNA damage and cancer

描述(由申请人提供)：基因表达最优雅和最严格调控的机制之一是可选的前-mRNA剪接。尽管调控剪接在几个发育过程和人类疾病中的重要性是毋庸置疑的，但人们对特定选择性剪接选择的调控机制知之甚少。重要的是，癌症中许多选择性剪接异构体的鉴定突显了剪接体在肿瘤表型中的潜在作用。最近，我们发现特定类型的细胞应激启动了p53调节剂MDM2和MDM4(MDMX)的协同选择性剪接。MDM2选择性转录本的主要活性是通过以显性负向方式抑制MDM2来激活P53通路。这些相同的替代转录本已经在许多人类肿瘤中被发现。我们有兴趣研究MDM2剪接的调控，以更好地了解1)在癌症中通过选择性剪接对P53通路的调控，2)癌症剪接体与癌症表型的关系，以及3)所产生的剪接形式在致癌中的作用。我们的数据表明，一些转化的细胞通过持续表达MDM2或剪接的转录本提供了激活P53的持续信号。这项拟议的研究将阐明RNA剪接、P53反应和最终癌症之间的分子联系。解开这一通路无疑将导致新的治疗干预点的发现，从而成为药物发现的重要踏脚石。

DESCRIPTION (provided by applicant): One of the most elegant and tightly regulated mechanisms for gene expression is alternative pre-mRNA splicing. Despite the undisputed importance of regulated splicing in several developmental processes and human disease, relatively little is known about the mechanisms by which specific alternative splice choices are regulated. Importantly, the identification of numerous alternatively spliced isoforms in cancer highlights the potential role of the spliceome in the tumor phenotype. Recently, we have shown that specific types of cell stress initiate coordinated alternative splicing of the p53 modulators mdm2 and mdm4 (mdmx). The predominant activity of the mdm2 alternative transcripts is to activate the p53 pathway by inhibiting MDM2 in a dominant negative fashion. These same alternative transcripts have been identified in numerous human tumors. We are interested in studying the regulation of mdm2 splicing to gain a better understanding of 1) regulation of the p53 pathway by alternative splicing in cancer 2) the relationship between the cancer spliceome and the cancer phenotype and 3) the role of the resultant spliced forms in the induction of cancer. Our data suggest that some transformed cells provide a constant signal to activate p53 through sustained expression of mdm2 alternatively spliced transcripts. The proposed research will elucidate the molecular connection between RNA splicing, the p53 response, and ultimately cancer. Unraveling this pathway will undoubtedly lead to the discovery of novel therapeutic intervention points and thus be a crucial stepping-stone for drug discovery.