Fig. 11

Summary of the oncogenic potential of TAZ in the mouse liver depending on its crosstalk with other genes. (A) Combined overexpression of myristoylated/activated AKT (AKT) and TAZS89A (a variant that escapes phosphorylation-mediated degradation by LATS1/2 proteins) drives the transdifferentiation of hepatocytes into malignant cholangiocytes, leading to intrahepatic cholangiocarcinoma development by 8-10 weeks post-injection. (B) Simultaneous overexpression of AKT and TAZS89AS51A (TAZS51A; a mutant form of TAZ that cannot bind to TEAD transcription factors) leads to the induction of clusters of lipid-rich and enlarged hepatocytes that are indistinguishable from those generated by transfection of AKT alone. (C) Overexpression of AKT and TAZS89A together with a dominant-negative form of the transcriptional regulator RBP-J (dnRBP-J) suppresses the NOTCH pathway, but does not impair AKT/TAZ-dependent liver carcinogenesis. Consequently, pure hepatocellular carcinoma lesions develop in AKT/TAZ/dnRBP-J mice by 13 weeks post-injection. (D) Suppression of YAP, the TAZ paralog, via short hairpin RNA delays cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Pure cholangiocarcinoma lesions form in AKT-shYAP-TAZ mice by 30 weeks post-injection. Abbreviations: w.p.i., weeks post-injection