Yes-associated protein 1 is activated and functions as an oncogene in meningiomas

Gilson S. Baia, Otavia L. Caballero, Brent A. Orr, Anita Lal, Janelle S Y Ho, Cynthia Cowdrey, Tarik Tihan, Christian Mawrin, Gregory J Riggins

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)904-913
Number of pages10
JournalMolecular Cancer Research
Volume10
Issue number7
DOIs
StatePublished - Jul 2012

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Meningioma
Oncogenes
Neurofibromin 2
Proteins
Cell Proliferation
Neoplasms
Carcinogenesis
Phosphorylation
Apoptosis
Tumor Suppressor Genes
Drosophila melanogaster
Nude Mice
Small Interfering RNA
Cisplatin
Cell Movement
Mammals
Cytoplasm
Homeostasis
Phosphotransferases

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Yes-associated protein 1 is activated and functions as an oncogene in meningiomas. / Baia, Gilson S.; Caballero, Otavia L.; Orr, Brent A.; Lal, Anita; Ho, Janelle S Y; Cowdrey, Cynthia; Tihan, Tarik; Mawrin, Christian; Riggins, Gregory J.

In: Molecular Cancer Research, Vol. 10, No. 7, 07.2012, p. 904-913.

Research output: Contribution to journalArticle

Baia, GS, Caballero, OL, Orr, BA, Lal, A, Ho, JSY, Cowdrey, C, Tihan, T, Mawrin, C & Riggins, GJ 2012, 'Yes-associated protein 1 is activated and functions as an oncogene in meningiomas', Molecular Cancer Research, vol. 10, no. 7, pp. 904-913. https://doi.org/10.1158/1541-7786.MCR-12-0116
Baia, Gilson S. ; Caballero, Otavia L. ; Orr, Brent A. ; Lal, Anita ; Ho, Janelle S Y ; Cowdrey, Cynthia ; Tihan, Tarik ; Mawrin, Christian ; Riggins, Gregory J. / Yes-associated protein 1 is activated and functions as an oncogene in meningiomas. In: Molecular Cancer Research. 2012 ; Vol. 10, No. 7. pp. 904-913.
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