Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC et al.. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA 103: 12405-12410

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2006; 103(33):12405-10. DOI: 10.1073/pnas.0605579103
Source: PubMed


In a screen for gene copy-number changes in mouse mammary tumors, we identified a tumor with a small 350-kb amplicon from a region that is syntenic to a much larger locus amplified in human cancers at chromosome 11q22. The mouse amplicon contains only one known gene, Yap, encoding the mammalian ortholog of Drosophila Yorkie (Yki), a downstream effector of the Hippo(Hpo)-Salvador(Sav)-Warts(Wts) signaling cascade, recently identified in flies as a critical regulator of cellular proliferation and apoptosis. In nontransformed mammary epithelial cells, overexpression of human YAP induces epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth in soft agar. Together, these observations point to a potential oncogenic role for YAP in 11q22-amplified human cancers, and they suggest that this highly conserved signaling pathway identified in Drosophila regulates both cellular proliferation and apoptosis in mammalian epithelial cells.

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    • "Indeed, in vitro work shows that both gain and loss of Hippo signaling components in a wide range of both non-cancer and cancer cell lines can enhance or suppress cancerous phenotypes [49,60-72]. Consistent for a central role of YAP/TAZ in the transforming properties of the Hippo pathway, the over-expression of YAP or TAZ in cell culture leads to transforming phenotypes including anchorage-independent growth, epithelial to mesenchymal transition, growth-factor independent proliferation, inhibition of apoptosis, resistance to chemotherapeutics, faster cell migration, tumor-initiation properties, invasion, and tumor formation in xenograft models [49,60-66]. Concordantly, removal of YAP or TAZ suppresses cancerous phenotypes in cancer cell lines [60-62,65-70]. "
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    ABSTRACT: Understanding the molecular nature of human cancer is essential to the development of effective and personalized therapies. Several different molecular signal transduction pathways drive tumorigenesis when deregulated and respond to different types of therapeutic interventions. The Hippo signaling pathway has been demonstrated to play a central role in the regulation of tissue and organ size during development. The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis, two key hallmarks in cancer development. The molecular nature of this pathway was first uncovered in Drosophila melanogaster through genetic screens to identify regulators of cell growth and cell division. The pathway is strongly conserved in humans, rendering Drosophila a suitable and efficient model system to better understand the molecular nature of this pathway. In the present study, we review the current understanding of the molecular mechanism and clinical impact of the Hippo pathway. Current studies have demonstrated that a variety of deregulated molecules can alter Hippo signaling, leading to the constitutive activation of the transcriptional activator YAP or its paralog TAZ. Additionally, the Hippo pathway integrates inputs from a number of growth signaling pathways, positioning the Hippo pathway in a central role in the regulation of tissue size. Importantly, deregulated Hippo signaling is frequently observed in human cancers. YAP is commonly activated in a number of in vitro and in vivo models of tumorigenesis, as well as a number of human cancers. The common activation of YAP in many different tumor types provides an attractive target for potential therapeutic intervention.
    Clinical and Translational Medicine 07/2014; 3(1):25. DOI:10.1186/2001-1326-3-25
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    • "Moreover, YAP expression levels affect the response to tamoxifen in specific breast cancer subtypes [30]. YAP depletion further sensitizes human cancer cells to anti-cancer agents, such as cisplatin or the EGFR tyrosine kinase inhibitor erlotinib [118], and increased YAP/TAZ levels correlate with taxol and cisplatin resistance [100,119,120]. Therefore, pharmacological inhibition of YAP/TAZ might be achieved through already available FDA-approved clinical compounds or combinations therewith. "
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    ABSTRACT: The Hippo tumour suppressor pathway co-ordinates cell proliferation, cell death and cell differentiation to regulate tissue growth control. In mammals, a conserved core Hippo signalling module receives signal inputs on different levels to ensure the proper regulation of YAP/TAZ activities as transcriptional co-activators. While the core module members MST1/2, Salvador, LATS1/2 and MOB1 have been attributed tumour suppressive functions, YAP/TAZ have been mainly described to have oncogenic roles, although some reports provided evidence supporting growth suppressive roles of YAP/TAZ in certain cancer settings. Intriguingly, mammalian Hippo signalling is also implicated in non-cancer diseases and plays a role in tissue regeneration following injury. Cumulatively, these findings indicate that the pharmacological inhibition or activation of the Hippo pathway could be desirable depending on the disease context. In this review, we first summarise the functions of the mammalian Hippo pathway in tumour formation, and then discuss non-cancer diseases involving Hippo signalling core components with a specific focus on our current understanding of the non-cancer roles of MST1/2 and YAP/TAZ. In addition, the pros and cons of possible pharmacological interventions with Hippo signalling will be reviewed, with particular emphasis on anti-cancer drug development and regenerative medicine.
    Clinical and Translational Medicine 07/2014; 3(1):22. DOI:10.1186/2001-1326-3-22
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    • "The YAP serine 127 to alanine (S127A) mutant is a constitutively active form that remains in the nucleus and is transcriptionally active. YAP regulates the balance between cell proliferation and apoptosis [18], [19], [20], and is amplified in a number of human malignancies including breast, esophageal, hepatocellular, ependymoma, malignant mesothelioma and medulloblastoma [21], [22], [23], [24], [25], [26]. In addition, YAP expression correlates with poor prognosis in various cancers, such as colorectal, esophageal, gastric, hepatocellular, lung and ovarian [22], [27], [28], [29], [30], [31], [32], "
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    ABSTRACT: Background Yes-associated protein (YAP) is a transcriptional co-activator and regulates cell proliferation and apoptosis. We investigated the clinical and biological significance of YAP in endometrial cancer (EMCA). Methods YAP expression in 150 primary tumor tissues from patients with EMCA was evaluated by immunohistochemistry and its association with clinicopathological data was assessed. The biological functions of YAP were determined in EMCA cell lines through knockdown/overexpression of YAP. The role of YAP in modulating radiation sensitivity was also investigated in EMCA cells. Results Increased nuclear YAP expression was significantly associated with higher grade, stage, lympho-vascular space invasion, postoperative recurrence/metastasis and overall survival in estrogen mediated EMCA, called type 1 cancer (p = 0.019, = 0.028, = 0.0008, = 0.046 and = 0.015, respectively). In multivariate analysis, nuclear YAP expression was confirmed as an independent prognostic factor for overall survival in type 1 EMCA. YAP knockdown by siRNA resulted in a significant decrease in cell proliferation (p<0.05), anchorage-dependent growth (p = 0.015) and migration/invasion (p<0.05), and a significant increase in the number of cells in G0/G1 phase (p = 0.002). Conversely, YAP overexpression promoted cell proliferation. Clonogenic assay demonstrated enhanced radiosensitivity by approximately 36% in YAP inhibited cells. Conclusions Since YAP functions as a transcriptional co-activator, its differential localization in the nucleus of cancer cells and subsequent impact on cell proliferation could have important consequences with respect to its role as an oncogene in EMCA. Nuclear YAP expression could be useful as a prognostic indicator or therapeutic target and predict radiation sensitivity in patients with EMCA.
    PLoS ONE 06/2014; 9(6):e100974. DOI:10.1371/journal.pone.0100974 · 3.23 Impact Factor
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