Yes-associated protein 1 is activated and functions as an oncogene in meningiomas
| Autor: | Anita Lal, Tarik Tihan, Otavia L. Caballero, Christian Mawrin, Gregory J. Riggins, Janelle S. Y. Ho, Brent A. Orr, Gilson Baia, Cynthia Cowdrey |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Apoptosis medicine.disease_cause Mice Cell Movement Neoplasms 2.1 Biological and endogenous factors Aetiology RNA Small Interfering Tissue homeostasis Cancer YAP1 Regulation of gene expression Pediatric Tumor Brain Neoplasms Adaptor Proteins Cell biology Gene Expression Regulation Neoplastic Oncology Hippo signaling Gene Knockdown Techniques Meningioma Tumor suppressor gene 1.1 Normal biological development and functioning Oncology and Carcinogenesis Biology Small Interfering Article Cell Line Experimental Rare Diseases Underpinning research Cell Line Tumor medicine Genetics otorhinolaryngologic diseases Animals Humans Oncology & Carcinogenesis Molecular Biology Adaptor Proteins Signal Transducing Cell Proliferation Hippo signaling pathway Neoplastic Wound Healing Signal Transducing YAP-Signaling Proteins Neoplasms Experimental Phosphoproteins Brain Disorders Merlin (protein) Brain Cancer Gene Expression Regulation Tissue Array Analysis Cancer research RNA Cisplatin Carcinogenesis Developmental Biology Transcription Factors |
| Zdroj: | Molecular cancer research : MCR, vol 10, iss 7 |
| ISSN: | 1557-3125 |
| Popis: | The Hippo signaling pathway is functionally conserved in Drosophila melanogaster and mammals, and its proposed function is to control tissue homeostasis by regulating cell proliferation and apoptosis. The core components are composed of a kinase cascade that culminates with the phosphorylation and inhibition of Yes-associated protein 1 (YAP1). Phospho-YAP1 is retained in the cytoplasm. In the absence of Hippo signaling, YAP1 translocates to the nucleus, associates with co-activators TEAD1-4, and functions as a transcriptional factor promoting the expression of key target genes. Components of the Hippo pathway are mutated in human cancers, and deregulation of this pathway plays a role in tumorigenesis. Loss of the NF2 tumor suppressor gene is the most common genetic alteration in meningiomas, and the NF2 gene product, Merlin, acts upstream of the Hippo pathway. Here, we show that primary meningioma tumors have high nuclear expression of YAP1. In meningioma cells, Merlin expression is associated with phosphorylation of YAP1. Using an siRNA transient knockdown of YAP1 in NF2-mutant meningioma cells, we show that suppression of YAP1 impaired cell proliferation and migration. Conversely, YAP1 overexpression led to a strong augment of cell proliferation and anchorage-independent growth and restriction of cisplatin-induced apoptosis. In addition, expression of YAP1 in nontransformed arachnoidal cells led to the development of tumors in nude mice. Together, these findings suggest that in meningiomas, deregulation of the Hippo pathway is largely observed in primary tumors and that YAP1 functions as an oncogene promoting meningioma tumorigenesis. Mol Cancer Res; 10(7); 904–13. ©2012 AACR. |
| Databáze: | OpenAIRE |
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