Induction of apoptosis in rhabdomyosarcoma cells through down-regulation of PAX proteins.
The expression of a number of human paired box-containing (PAX) genes has been correlated with various types of tumors. Novel fusion genes encoding chimeric fusion proteins have been found in the pediatric malignant tumor alveolar rhabdomyosarcoma (RMS). They are generated by two chromosomal translocations t(2;13) and t(1;13) juxtaposing PAX3 or PAX7, respectively, with a forkhead domain gene FKHR. Here we describe that specific down-regulation of the t(2;13) translocation product in alveolar RMS cells by antisense oligonucleotides results in reduced cellular viability. Cells of embryonal RMS, the other major histiotype of this tumor, were found to express either wild type PAX3 or PAX7 at elevated levels when compared with primary human myoblasts. Treatment of corresponding embryonal RMS cells with antisense olignucleotides directed against the mRNA translational start site of either one of these two transcription factors similarly triggers cell death, which is most likely due to induction of apoptosis. Retroviral mediated ectopic expression of mouse Pax3 in a PAX7 expressing embryonal RMS cell line could partially rescue antisense induced apoptosis. These data suggest that the PAX3/FKHR fusion gene and wild-type PAX genes play a causative role in the formation of RMS and presumably other tumor types, possibly by suppressing the apoptotic program that would normally eliminate these cells.
Bernasconi
M
M
Department of Pediatrics, University of Zürich, Switzerland.
Remppis
A
A
Fredericks
W J
WJ
Rauscher
F J
FJ
Schäfer
B W
BW
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002878:Chromosomes, Human, Pair 1; D002882:Chromosomes, Human, Pair 13; D002889:Chromosomes, Human, Pair 2; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D014157:Transcription Factors; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D051761:Paired Box Transcription Factors; C497322:Pax7 protein, mouse; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C068686:Pax3 protein, mouse