Transformation of normal cells by aberrant activation of YAP via cMyc with TEAD.

YAP (also known as YAP1 or YAP65) is a transcriptional coactivator that interacts with a number of transcription factors including RUNX and TEAD and plays a pivotal role in controlling cell growth. YAP is classified as a proto-oncogene. However, the mechanism by which activated YAP induces cancerous changes is not well known. Here we demonstrate that overexpression of YAP in NIH3T3 cells was sufficient for inducing tumorigenic transformation of cells. Mechanistically, YAP exerts its function in cooperation with the TEAD transcription factor. Our data also show that cMYC is a critical factor that acts downstream of the YAP/TEAD complex. Furthermore, we also found that aberrant activation of YAP is sufficient to drive tumorigenic transformation of non-immortalized mouse embryonic fibroblasts. Together our data indicate that YAP can be categorized as a new type of proto-oncogene distinct from typical oncogenes, such as H-RAS, whose expression in non-immortalized cells is tightly linked to senescence.