title: Yes-associated protein 1 is activated and functions as an oncogene in meningiomas.
abstract: 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.
authors.affiliation: Ludwig Collaborative Laboratory, Neurosurgery Department, The Johns Hopkins University, Baltimore, MD 21231, USA. gbaia1@jhmi.edu
authors.forename: Gilson S
authors.initials: GS
authors.lastname: Baia
authors.forename: Otavia L
authors.initials: OL
authors.lastname: Caballero
authors.forename: Brent A
authors.initials: BA
authors.lastname: Orr
authors.forename: Anita
authors.initials: A
authors.lastname: Lal
authors.forename: Janelle S Y
authors.initials: JS
authors.lastname: Ho
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cowdrey
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Christian
authors.initials: C
authors.lastname: Mawrin
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008579:Meningioma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D046888:Tissue Array Analysis; D014157:Transcription Factors; D014945:Wound Healing; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D002945:Cisplatin