Heterogeneous ribonucleoprotein A1 is part of an exon-specific splice-silencing complex controlled by oncogenic signaling pathways

Regulation of alternative pre-mRNA splicing, recognized as increasingly imp ortant in causing human disease, was studied using the CD44 gene, whose spl ice variants have been implicated in tumor progression. We identified heter ogeneous ribonucleoprotein (hnRNP) Al as a protein interacting in vitro and in vivo with regulatory splice elements in CD44 variant exon v5, Transient overexpression of hnRNP Al prevented v5 exon inclusion, dependent on the e xonic elements. HnRNP Al-dependent repression was exon-specific and could b e relieved by coexpression of oncogenic forms of Ras and Cdc42, The results define hnRNP Al as a decisive part of an oncogene-regulated splice-silenci ng complex, which can select between multiple alternatively spliced exons.