Open AccessInduction of apoptosis in rhabdomyosarcoma cells through down-regulation of PAX proteins
Author(s) -
Michele Bernasconi,
Andrew Remppis,
William J. Fredericks,
Frank J. Rauscher,
Beat W. Schäfer
Publication year - 1996
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.93.23.13164
Subject(s) - alveolar rhabdomyosarcoma , pax3 , biology , fusion gene , rhabdomyosarcoma , embryonal rhabdomyosarcoma , fusion protein , microbiology and biotechnology , apoptosis , gene , ectopic expression , transfection , cell culture , gene expression , cancer research , transcription factor , genetics , sarcoma , recombinant dna , pathology , medicine
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) juxtaposingPAX3 orPAX7 , respectively, with a forkhead domain geneFKHR . 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 typePAX3 orPAX7 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 mousePax3 in aPAX7 expressing embryonal RMS cell line could partially rescue antisense induced apoptosis. These data suggest that thePAX3 /FKHR fusion gene and wild-typePAX 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.