The Hippo signaling pathway is a well-conserved pathway that controls tissue homeostasis and organ size. Activation of an upstream phosphorylation cascade through this pathway leads to the suppression of the transcriptional co-activators YAP/YAP1 and TAZ/WWTR1. Because these two proteins regulate the transcription of genes involved in cell proliferation, apoptosis, and stem cell self-renewal, precise control of their activity and abundance is imperative for normal development and organismal homeostasis. Indeed, altered expression or inactivation of Hippo pathway genes has been observed in many human cancer patient samples and has been shown to drive tumorigenesis in mouse models. Despite the established importance of Hippo signaling in cancer, there still remains a lack of complete characterization of Hippo pathway regulation as few mutations in the pathway are found in human cancers, suggesting the role of other upstream inputs and signaling cross talk. The goal of this proposal is to identify and characterize novel regulators of the Hippo pathway effectors YAP/TAZ to gain a more comprehensive understanding of the Hippo signaling network as it pertains to normal cellular physiology and cancer progression. To gain insight into the regulation of YAP/TAZ, I have performed a gene-trap mutagenesis screen in a haploid cell line expressing a TAZ-fluorescent fusion protein. Unexpectedly, a number of RNA-binding proteins were identified from the screen. Because one gene candidate DHX29, an RNA helicase reported to promote translation and play a role in cell proliferation, had the most robust phenotype upon validation and correlated strongly with YAP/TAZ levels across a panel of cancer cell lines, this proposal will seek to characterize the role of translational regulation on YAP/TAZ activity and its impact on YAP/TAZ- mediated tumorigenesis.
Aim 1 will determine the functional role of DHX29 on the regulation of YAP/TAZ activity.
Aim 2 will characterize its role in YAP/TAZ-mediated tumorigenesis. Successful completion of the proposed research will elucidate a novel regulatory mechanism of the Hippo pathway effectors in the context of tumor development. As activation of YAP/TAZ in different tissues in mouse models suggests the role of the Hippo pathway in cancer initiation and progression, characterizing a novel regulatory network will inform mechanisms of cancer pathogenesis and identify potential therapeutic handles for modulating tumor progression.
The Hippo signaling pathway is a master regulator of organ size: it is essential for normal development and its dysregulation leads to cancer. Because this pathway is mediated by precise control of the major downstream genes YAP and TAZ, deciphering the complete network underlying their regulation will be fundamental to understanding cancer and informing potential treatments. The goal of this proposal is to characterize novel regulators of YAP/TAZ in the context of cancer using experimental bench work and pre-clinical mouse models.
