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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132809-05
Application #
8215749
Study Section
Special Emphasis Panel (ZRG1-ICI-D (01))
Program Officer
Watson, Joanna M
Project Start
2008-04-08
Project End
2013-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$310,970
Indirect Cost
$109,695
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Zha, Zhengyu; Han, Xiao-Ran; Smith, Matthew D et al. (2016) Hypertension-associated C825T polymorphism impairs the function of Gβ3 to target GRK2 ubiquitination. Cell Discov 2:16005
Yang, Hui; Zhou, Lisha; Shi, Qian et al. (2015) SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth. EMBO J 34:1110-25
Taniguchi, Koji; Wu, Li-Wha; Grivennikov, Sergei I et al. (2015) A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519:57-62
Moroishi, Toshiro; Park, Hyun Woo; Qin, Baodong et al. (2015) A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev 29:1271-84
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 57:662-73
Moroishi, Toshiro; Hansen, Carsten Gram; Guan, Kun-Liang (2015) The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 15:73-9
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 13:2353-61
Yu, Fa-Xing; Zhao, Bin; Guan, Kun-Liang (2015) Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell 163:811-28
Yu, Fa-Xing; Meng, Zhipeng; Plouffe, Steven W et al. (2015) Hippo pathway regulation of gastrointestinal tissues. Annu Rev Physiol 77:201-27

Showing the most recent 10 out of 48 publications