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Alveolar rhabdomyosarcoma-associated PAX3-FOX01 promotes tumorigenesis via Hippo pathway suppression.

Authors :
Crose, Lisa E.S.
Galindo, Kathleen A.
Kephart, Julie Grondin
Chen, Candy
Fitamant, Julien
Bardeesy, Nabeel
Bentley, Rex C.
Galindo, Rene L.
Chi, Jen-Tsan Ashley
Linardic, Corinne M.
Source :
Journal of Clinical Investigation. Jan2014, Vol. 124 Issue 1, p285-296. 12p. 6 Graphs.
Publication Year :
2014

Abstract

Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the paired box 3-forkhead box protein Ol (PAX3-FOX01) fusion oncogene. Despite its discovery nearly two decades ago, the mechanisms by which PAX3-FOX01 drives tumor development are not well characterized. Previously, we reported that PAX3-FOX01 supports aRMS initiation by enabling bypass of cellular senescence checkpoints. We have now found that this bypass occurs in part through PAX3-FOX01-medi-ated upregulation of RASSF4, a Ras-association domain family (RASSF) member. RASSF4 expression was upregulated in PAX3-FOX01 -positive aRMS cell lines and tumors. Enhanced RASSF4 expression promoted cell cycle progression, senescence evasion, and tumorigenesis through inhibition of the Hippo pathway tumor suppressor MST1. We also found that the downstream Hippo pathway target Yes-associated protein 1 (YAP), which is ordinarily restrained by Hippo signaling, was upregulated in RMS tumors. These data suggest that Hippo pathway dysfunction promotes RMS. This work provides evidence for Hippo pathway suppression in aRMS and demonstrates a progrowth role for RASSF4. Additionally, we identify a mechanism used by PAX3-FOXOl to inhibit MST1 signaling and promote tumorigenesis in aRMS. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00219738
Volume :
124
Issue :
1
Database :
Academic Search Index
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
93515999
Full Text :
https://doi.org/10.1172/JCI67087