Regulation of RacI alternative splicing

FEDERICO PELISCH; MATÍAS BLAUSTEIN; LEANDRO QUADRANA; DEREK RADISKY; ANABELLA SREBROW

Oxford, Reino Unido

Conferencia; Gordon Research Conference: “The Biology of Post-Trancriptional Gene Regulation”; 2006

Rac1 is a member of the Ras superfamily of small GTPases. When activated, Rac1 stimulates alterations in the organization of the cytoskeleton, cell proliferation, and the activation of many signaling pathways. Rac1b, an alternatively spliced variant of Rac1 containing a 57-nt insertion (exon 3b), is a constitutively active isoform identified in malignant breast and colorectal tumors. Rac1b has been shown to promote cellular transformation in culture, although no mechanism for controlling exon 3b inclusion has been identified. Stromelysin-1/matrix metalloproteinase-3 (MMP-3), a stromal enzyme upregulated in many breast tumours, was found to cause epithelial-to-mesenchymal transition (EMT) and malignant transformation in cultured cells. Radisky et al have shown recently that exposure of normal mouse mammary epithelial cells (SCp2) to MMP-3 induces the expression of Rac1b (fig. 1A), and specific siRNA-mediated knockdown of this isoform prevents MMP-3-induced EMT (Nature 436:123-7 - 2005, fig. 1B).