Date of Award
Doctor of Philosophy (PhD)
Pathology & Microbiology
The Hippo pathway controls organ size and tumorigenesis by inhibiting cell proliferation and promoting apoptosis. KIBRA [kidney and brain expressed protein] is an upstream regulator of the Hippo-YAP signaling. The role KIBRA plays in mitosis has not been established. We show that KIBRA activates the Aurora kinases during mitosis and KIBRA promotes the phosphorylation of large tumor suppressor 2 by activating Aurora-A. We further show that knockdown of KIBRA causes mitotic abnormalities, including defects of spindle and centrosome formation and chromosome misalignment. The transcriptional co-activator with PDZ-binding motif is a downstream effector of the Hippo tumor suppressor pathway. In the current study, we define a new layer of regulation of TAZ activity that is critical for its oncogenic function. We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, the non-phosphorylatable mutant possesses higher activity in epithelial-mesenchymal transition, anchorage-independent growth, cell migration and invasion. Functional studies show that the non-phosphorylatable mutant of TAZ was sufficient to induce spindle and centrosome defects in immortalized epithelial cells. Together, our results reveal a previously unrecognized connection between TAZ oncogenicity and mitotic phospho-regulation.
Recent studies have demonstrated that the Hippo signaling pathway plays a critical role in tumorigenesis. The functional significance of the main effector of the Hippo tumor suppressor pathway, YAP, in prostate cancer has remained elusive. We show that enhanced expression of YAP transformed immortalized prostate epithelial cells and promoted migration and invasion in both immortalized and cancerous prostate cells. YAP knockdown largely blocked cell division in LNCaP-C4-2 cells under androgen-deprivation conditions. In addition, ectopic expression of YAP was sufficient to promote LNCaP cells from androgen-sensitive to androgen-insensitive in vitro and YAP conferred castration resistance in vivo. Our results identify YAP as a novel regulator in prostate cancer and as a potential therapeutic target for castration-resistant prostate cancer.
Zhang, Lin, "Role of Hippo-YAP signaling in Mitosis and Prostate Cancer" (2015). Theses & Dissertations. 2.
Available for download on Saturday, June 03, 2017