Abstract
PAX3-FOXO1 (PAX3-FKHR) is the fusion protein produced by the genomic translocation that characterizes the alveolar subtype of Rhabdomyosarcoma, a pediatric sarcoma with myogenic phenotype. PAX3-FOXO1 is an aberrant but functional transcription factor. It retains PAX3-DNA-binding activity and functionally overlaps PAX3 function while also disturbing it, in particular its role in myogenic differentiation. We herein show that PAX3-FOXO1 interferes with normal FOXO function. PAX3-FOXO1 affects FOXO-family member trans-activation capability and the FOXO-dependent TGF-β response. PAX3-FOXO1 may contribute to tumor formation by inhibiting the tumor suppressor activities which are characteristic of both FOXO family members and TGF-β pathways. The recognition of this mechanism raises new questions about how FOXO family members function.
Highlights
Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma with myogenic phenotype, and is the most common soft-tissue sarcoma in children, adolescents and young adults [1]
A mutation of the human FOXO ortholog, daf-16, in C.elegans reverts the lifetime extension caused by mutations in the insulin receptor or in PI3K, which highlights its crucial role in these pathways
Evidence of FOXOs' direct involvement in tumorigenesis has been concealed by the fact that FOXO1, FOXO3 and FOXO4 are redundant
Summary
Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma with myogenic phenotype, and is the most common soft-tissue sarcoma in children, adolescents and young adults [1]. Most (75%) ARMS cases display recurrent chromosomal translocation that fuses two transcription factor-encoding genes together; the PAX3 gene (in a minority of cases the PAX7 gene) and the FOXO1 gene [2]. PAX3-FOXO1 has been extensively studied (reviewed in [3,4]), and functional studies have confirmed its active role in ARMS generation. Its N-terminal encompasses the PAX3 DNAbinding domains (paired and homeo domain) and is fused to the C-terminal of FOXO1 which comprises the truncated FOXO1 DNA-binding domain and the FOXO1 C-terminal transcriptional transactivation domain. PAX3-FOXO1 retains PAX3-DNA-binding activity and is capable of initiating a transcription program which overlaps, but is distinct from, the program generated by PAX3. PAX3-FOXO1 can promote partial myogenic differentiation in certain cellular contexts [6,7], but is able
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