Le Hir Hervé, Charlet-Berguerand Nicolas, de Franciscis Vittorio, Thermes Claude
Centre de Génétique Moléculaire, Laboratoire associé à l'Université Pierre et Marie Curie, Gif-sur-Yvette, France.
Oncology. 2002;63(1):84-91. doi: 10.1159/000065725.
The Ret tyrosine kinase is implicated in neuronal cell survival, kidney development and tumorigenesis. Several 3' and 5' transcript variants have been described resulting from alternative splicing of the RET pre-mRNA. The 3' variants code for three C-terminal isoforms, RET51, RET9 and RET43. The 5' variants RET2/4, RET2/5 and RET2/6 result from skipping exons 3, 3-4 and 3-5, respectively. These variants code for putative Ret proteins differing in their extracellular ligand-binding domains, and their expression is strongly regulated during kidney development. Here we analyzed the presence of these RET 5' variants in normal tissues and in MEN2 and sporadic pheochromocytomas. In all tissues examined, the abundance of these transcripts remained extremely low (less than 1% of all RET transcripts) thus indicating these species as rare variants with little biological meaning. On the other hand, in tumors, the 5' RET splicing pattern differed from that of normal tissues. Indeed, we identified a RET-derived transcript that results from the aberrant retention of intron 2. This transcript is enriched in tumor samples of both familial and sporadic origin, and indicates RET as a target for RNA splicing deregulation in tumor cells.
Ret酪氨酸激酶与神经元细胞存活、肾脏发育和肿瘤发生有关。已描述了几种由RET前体mRNA的可变剪接产生的3'和5'转录变体。3'变体编码三种C末端异构体，即RET51、RET9和RET43。5'变体RET2/4、RET2/5和RET2/6分别是由于外显子3、3-4和3-5的跳跃而产生的。这些变体编码在细胞外配体结合域不同的假定Ret蛋白，并且它们的表达在肾脏发育过程中受到强烈调控。在这里，我们分析了这些RET 5'变体在正常组织以及MEN2和散发性嗜铬细胞瘤中的存在情况。在所有检测的组织中，这些转录本的丰度仍然极低（占所有RET转录本的不到1%），因此表明这些变体是罕见的，几乎没有生物学意义。另一方面在肿瘤中，5' RET剪接模式与正常组织不同。实际上，我们鉴定出一种由内含子2异常保留产生的源自RET的转录本。这种转录本在家族性和散发性起源肿瘤样本中均富集，表明RET是肿瘤细胞中RNA剪接失调的一个靶点。
