THE ROLE OF THE HIPPO PATHWAY IN ONCOGENIC TRANSFORMATION

Abstract

The tumorigenic capacity of oncogenes like RasV12 is kept in check in primary cells by activation of tumor suppressor pathways. Yet, inactivation of the p53 and pRb tumor suppressors, concomitant with RasV12 and hTert expression, is insufficient to support anchorage independent growth and tumorigenesis in vivo. We show that RasV12 additionally activates the conserved Hippo tumor suppressor pathway in primary human fibroblast and epithelial cells. This is overruled by the SV40 Small T oncogene, which activates PAK1 and inhibits NF2/Merlin. Overcoming the Hippo pathway mediated inactivation of the transcriptional co-activator YAP is necessary and sufficient to specifically allow anchorage independent growth, uncovering the Hippo pathway as a key gatekeeper to transformation and tumorigenesis in primary human cells.