Regulation and function of the YAP transcription co-activator oncoprotein The yes-associated protein YAP is a potent transcription co-activator. Recent genetic studies have implicated YAP as a candidate oncogene in human chromosome 11q22 amplicon. Drosophila studies have established a novel tumor suppressor pathway Hippo that regulates both cell proliferation and apoptosis. Many components of the Hippo pathway are highly conserved. YAP is likely to be the major target inhibited by the Hippo pathway. YAP can functionally rescue yorkie (the Drosophila homolog of mammalian YAP) mutation in Drosophila. It has been suggested that the neurofibromatosis 2 (NF2) tumor suppressor is a component of the Hippo pathway acting upstream of YAP to inhibit YAP function. However, the Hippo pathway has not been investigated in mammalian cells. The long term goals of this project are to determine the function and regulation of the Hippo pathway in development of human cancers. Our preliminary data have shown that the Hippo-YAP pathway plays an essential role in cell contact inhibition and oncogenic transformation. Furthermore, YAP is highly elevated in human cancers, including prostate and liver cancers.
The specific aims of this proposal are: 1. To identify and characterize YAP target transcription factors 2. To determine the function of YAP target transcription factors in cell contact inhibition, oncogenic transformation, and epithelial-mesenchymal transition 3. To determine the function of YAP-induced micro RNA Public Health Relevance: YAP is a transcription co-activator and oncogene highly elevated in human cancers. This proposal will study the molecular mechanism of YAP in tumorigenesis by promoting cell proliferation and inhibiting cell death.
|Zhang, Qian; Meng, Fansen; Chen, Shasha et al. (2017) Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade. Nat Cell Biol 19:362-374|
|Hong, Audrey W; Meng, Zhipeng; Guan, Kun-Liang (2016) The Hippo pathway in intestinal regeneration and disease. Nat Rev Gastroenterol Hepatol 13:324-37|
|Han, X-R; Zha, Z; Yuan, H-X et al. (2016) KDM2B/FBXL10 targets c-Fos for ubiquitylation and degradation in response to mitogenic stimulation. Oncogene 35:4179-90|
|Zha, Zhengyu; Han, Xiao-Ran; Smith, Matthew D et al. (2016) Hypertension-associated C825T polymorphism impairs the function of G?3 to target GRK2 ubiquitination. Cell Discov 2:16005|
|Yu, Fa-Xing; Zhao, Bin; Guan, Kun-Liang (2015) Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell 163:811-28|
|Ma, Shenghong; Jiang, Bowen; Deng, Wanglong et al. (2015) D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth. Oncotarget 6:8606-20|
|Wang, Yiping; Xiao, Mengtao; Chen, Xiufei et al. (2015) WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Mol Cell 57:662-673|
|Plouffe, Steven W; Hong, Audrey W; Guan, Kun-Liang (2015) Disease implications of the Hippo/YAP pathway. Trends Mol Med 21:212-22|
|Wang, Pu; Wu, Jing; Ma, Shenghong et al. (2015) Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents. Cell Rep 13:2353-2361|
|Park, Hyun Woo; Kim, Young Chul; Yu, Bo et al. (2015) Alternative Wnt Signaling Activates YAP/TAZ. Cell 162:780-94|
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