Coordinately regulated alternative splicing in DNA damage and cancer

描述（由申请人提供）：基因表达的最优雅和最严格调控的机制之一是选择性前mRNA剪接。尽管调控剪接在几个发育过程和人类疾病中具有无可争议的重要性，但对特定的选择性剪接选择的调控机制知之甚少。重要的是，在癌症中鉴定出许多选择性剪接的同种型突出了剪接体在肿瘤表型中的潜在作用。最近，我们已经表明，特定类型的细胞应激启动协调的选择性剪接的p53调制器mdm2和mdm4（mdmx）。mdm2替代转录物的主要活性是通过以显性负性方式抑制MDM2来激活p53途径。这些相同的替代转录物已在许多人类肿瘤中被鉴定。我们有兴趣研究mdm2剪接的调节，以更好地理解1）癌症中选择性剪接对p53通路的调节，2）癌症剪接体与癌症表型之间的关系，以及3）所得剪接形式在诱导癌症中的作用。我们的数据表明，一些转化细胞提供了一个恒定的信号，通过持续表达mdm2选择性剪接转录激活p53。这项拟议中的研究将阐明RNA剪接、p53反应和最终癌症之间的分子联系。解开这一途径无疑将导致新的治疗干预点的发现，从而成为药物发现的关键垫脚石。 公共卫生相关性：p53是最重要的肿瘤抑制基因之一，其正常功能是防止不适当的细胞生长和增殖。这项拟议中的研究将破译选择性剪接在p53通路的转化和破坏中的作用。由于p53肿瘤抑制通路的激活是癌症治疗的中心目标，因此了解剪接有助于其沉默的方式可能会导致新的治疗方法来反应p53肿瘤抑制活性。

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. PUBLIC HEALTH RELEVANCE: p53 is one of the most important tumor suppressor genes whose normal function is to prevent inappropriate cell growth and proliferation. The proposed research will decipher the role of alternative splicing in transformation and disruption of the p53 pathway. Since activation of the p53 tumor suppressor pathway is a central target for cancer therapy, understanding the way that splicing contributes to its silencing could lead to novel therapies to reactive the p53 tumor suppressor activity.