A study of the Hippo pathway/Yap biology and its functions in proliferation control.

摘要

Understanding how cells control cell sizes and proliferation provides crucial insights into the fundamentals of life and has major implications for regenerative and cancer therapeutics. My thesis project studies the mechanisms underlying the Hippo pathway mediated proliferation and cell cycle regulation. My research work elucidates how the Hippo pathway functions through its downstream effector, Yes-associate protein (Yap), using a combination of mouse genetics and cell-based in vitro systems. The results demonstrate that Yap requires Angiomotin isoform p130 (Amot p130) as a co-factor to function in target transcriptional activation. Consequently, Yap-dependent hepatoma becomes less aggressive upon the loss of Amot p130. Significantly, the findings help to clarify the controversy regarding the Yap and Angiomotin relationship in the Hippo pathway. This thesis also investigates the role of Yap in cell proliferation control using in vitro systems. Remarkably, Yap is required for endothelial cell proliferation, and likely through modulating the expression of G1-to-S transition genes. Genome array studies also implicate Yap in double stranded DNA break repair and homologous recombination occurred during DNA replication. Taken together, these results provide new insight into the biology of Yap and the mechanisms through which the Hippo pathway regulates proliferation.