Regulation and functional effects of localized RNAs

大量的RNA并不弥散分布在细胞质中，而是被主动转运到各种亚细胞位点。到达最终目的地后，定位的RNA被翻译，从而指导局部蛋白质的产生。虽然越来越多的本地化RNA被确定，这些事件的功能的重要性还没有得到很好的理解。我们专注于我们已经确定的定位途径，该途径将许多RNA靶向细胞突起的尖端。我们已经发现，这一途径的一个重要组成部分是肿瘤抑制蛋白腺瘤性结肠息肉病（APC），其突变是大多数结直肠癌进展的起始事件。APC与RNA在核糖核蛋白复合物中的细胞突起处结合，我们称之为APC-RNP。APC-RNP的另一个组成部分是RNA结合蛋白Fus/TLS，这种蛋白质的突变与癌症和肌萎缩侧索硬化症有关。我们最近发现，ALS相关的突变体Fus错误定位APC-RNP在内部细胞质颗粒和误导他们的翻译。我们正在使用方法分离局部合成的蛋白质，并确定RNA的错误定位和错误翻译如何影响蛋白质的性质和功能。我们还在研究这些局部RNA是如何受到影响的，以及它们在多大程度上促进了结直肠癌的进展。

A large number of RNAs are not diffusely distributed in the cytoplasm, but are actively transported to various subcellular sites. After reaching their final destinations, localized RNAs are translated thus directing local protein production. While increasing numbers of localized RNA are being identified, the functional importance of these events is not well understood. We are focusing on a localization pathway that we have identified, which targets a number of RNAs to the tips of cellular protrusions. We have found that an important component of this pathway is the tumor-suppressor protein Adenomatous Polyposis Coli (APC) whose mutation is the initiating event in the progression of the majority of colorectal cancers. APC associates with RNAs at cellular protrusions in ribonucleoprotein complexes, which we term APC-RNPs. An additional component of APC-RNPs is the RNA-binding protein Fus/TLS, a protein whose mutation has been linked to both cancer and Amyotrophic Lateral Sclerosis. We have recently shown that ALS-associated mutants of Fus mislocalize APC-RNPs in internal cytoplasmic granules and misdirect their translation. We are using methods to isolate locally synthesized proteins and determine how RNA mislocalization and misdirection of translation affects protein properties and function. We are additionally addressing how these localized RNAs are affected and to what extent they contribute to colorectal cancer progression.