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| Status |
Public on May 15, 2014 |
| Title |
PAX3-FOXO1 suppresses cellular senescence through RASSF4-mediated restraint of the mammalian Hippo/MST1 pathway |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the PAX3-FOXO1 fusion gene. Despite its discovery over almost 20 years ago, PAX3-FOXO1 remains an enigmatic tumor driver. Previously, we reported that PAX3-FOXO1 supports aRMS initiation by enabling bypass of cellular senescence. Here, we show that bypass occurs in part by PAX3-FOXO1-mediated upregulation of RASSF4, a Ras-association domain family (RASSF) member, which then suppresses the evolutionarily conserved mammalian Hippo/Mst1 pathway. RASSF4 loss-of-function activates Hippo/Mst1 and inhibits downstream YAP, causing aRMS cell cycle arrest and senescence. This is the first evidence for an oncogenic role for RASSF4, and a novel mechanism for Hippo signaling suppression in human cancer.
Human skeletal muscle myoblasts (HSMMs) were retrovirally transduced with either an empty vector (Vp, pK1) or PAX3-FOXO1 (PFp, pK1-PAX3-FOXO1) and selected on puromycin. Presenescent (presen) cells were harvested before the senescence checkpoint. Since cells expressing PAX3-FOXO1 can bypass the senescence checkpoint, postsenescent (postsen) cells expressing PAX3-FOXO1 were also harvested.
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| |
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| Overall design |
the gene expression affected by the introduction of PAX3-FOXO1
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| |
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| Contributor(s) |
Crose LE, Chi JA, Linardic CM |
| Citation(s) |
24334454 |
| Submission date |
Aug 31, 2012 |
| Last update date |
Dec 06, 2018 |
| Contact name |
Jen-Tsan Chi |
| E-mail(s) |
jentsan.chi@duke.edu
|
| Phone |
919-668-4759
|
| Organization name |
Duke University
|
| Department |
Molecular Genetics and Microbiology
|
| Street address |
101 Science Drive, DUMC 3382
|
| City |
Durham |
| State/province |
NC |
| ZIP/Postal code |
27708 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL571 |
[HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array |
|
| Samples (9)
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| Relations |
| BioProject |
PRJNA174363 |
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