cDNA microarrays detect activation of a myogenic transcription program by the<i>PAX3-FKHR</i>fusion oncogene

Khan, Javed; Bittner, Michael; Saal, Lao H.; Teichmann, Ulrike; Azorsa, David O.; Gooden, Gerald C.; Pavan, William J.; Trent, Jeffrey M.; Meltzer, Paul S.

doi:10.1073/pnas.96.23.13264

Cited by 292 publications

(139 citation statements)

References 35 publications

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“…This expression pattern resembles our PAX3-FKHRexpressing populations. Khan et al (1999) reported similar results using expression arrays. PAX3-FKHR has also been shown to transactivate myogenin directly, independent of MyoD (Zhang and Wang, 2007).…”

Section: Discussionsupporting

confidence: 55%

“…An intriguing property of these proteins is their ability to regulate myogenesis. Expression array studies have shown that PAX3-FKHR induces a myogenic expression pattern (Khan et al, 1999). Perhaps paradoxical, PAX3-FKHR can also inhibit C2C12 myoblasts and MyoD-expressing 10T1/2 fibroblasts from terminally differentiating (Epstein et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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PAX-FKHR function as pangenes by simultaneously inducing and inhibiting myogenesis

et al. 2007

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Alveolar rhabdomyosarcomas (ARMS) escape terminal differentiation despite exhibiting a skeletal muscle phenotype. To understand the role of the ARMS-specific PAX-FKHR proteins in myogenesis, we characterized their regulation of MyoD expression and function. Reporter assays show that PAX-FKHR transactivate MyoD expression through its 258 bp core enhancer. Gel-shift assays confirm that PAX-FKHR bind to core enhancer sequences showing similarity to consensus PAX3/PAX-FKHRbinding sites. We show that while PAX3-FKHR activates the expression of endogenous MyoD and myogenin proteins in transduced NIH3T3 fibroblasts, it inhibits them from terminally differentiating as shown by low myogenin and myosin heavy chain expression, and lack of myotube formation. Attenuation of MyoD transcriptional activity via phosphorylation coupled to the lack of cell cycle arrest is the underlying mechanism for the differentiation block. Lastly, we show that fibroblast growth factor receptor signaling likely mediates the inhibition of differentiation by PAX3-FKHR. In a single experimental system we demonstrate that PAX3-FKHR can simultaneously induce myogenesis while preventing its completion. We propose a model whereby PAX-FKHR commit a yet undefined precursor cell to the myogenic lineage while at the same time inhibit terminal differentiation, thereby contributing to ARMS formation.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

PAX-FKHR function as pangenes by simultaneously inducing and inhibiting myogenesis

et al. 2007

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“…On the other hand, the transience of PAX3-FOXO1 RNA is consistent with the normal process of muscle differentiation, as prolonged production of PAX3-FOXO1 RNA leads to constant expression of MYOD and MYOG , which then blocks terminal differentiation ( 13,14 ). We reasoned that a posttranscriptional process, such as trans -splicing of precursor mRNAs, can give rise to transient, temporal appearance of the fusion product ( 16,17 ), whereas gene fusions caused by chromosomal translocation result in constitutive synthesis of chimeric PAX3-FOXO1 RNA, and in turn MYOD and MYOG expression that permanently arrests myocytes at immature forms, which can potentially lead to ARMS if combined with secondary mutations.…”

Section: Discussionmentioning

confidence: 87%

“…Studies in fi broblast and rhabdomyosarcoma cell lines have demonstrated that the PAX3-FOXO1 protein simultaneously induces myogenesis while blocking differentiation to mature muscle, thereby contributing to the formation of ARMS ( 13,14 ). To test the effect of constant expression of PAX3-FOXO1 in the muscle differentiation setting, MSC cells were infected with retroviral vectors that overexpress PAX3-FOXO1 ( Fig.…”

Section: Research Articlementioning

confidence: 99%

A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process

et al. 2013

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Gene fusions and their chimeric products are common features of neoplasia. Given that many cancers arise by the dysregulated recapitulation of processes in normal development, we hypothesized that comparable chimeric gene products may exist in normal cells. Here, we show that a chimeric RNA, PAX3-FOXO1 , identical to that found in alveolar rhabdomyosarcoma, is transiently present in cells undergoing differentiation from pluripotent cells into skeletal muscle. Unlike cells of rhabdomyosarcoma, these cells do not seem to harbor the t(2;13) chromosomal translocation. Importantly, both PAX3-FOXO1 RNA and protein could be detected in the samples of normal fetal muscle. Overexpression of the chimera led to continuous expression of MYOD and MYOG-two myogenic markers that are overexpressed in rhabdomyosarcoma cells. Our results are consistent with a developmental role of a specifi c chimeric RNA generated in normal cells without the corresponding chromosomal rearrangement at the DNA level seen in neoplastic cells presumably of the same lineage. SIGNIFICANCE:A chimeric fusion RNA, PAX3-FOXO1 , associated with alveolar rhabdomyosarcoma, is also present in normal non-cancer cells and tissues. Its transient expression nature and the absence of t(2;13) chromosomal translocation are consistent with a posttranscriptional mechanism. When constantly expressed, PAX3-FOXO1 interfered with the muscle differentiation process, which presumably contributes to tumorigenesis.

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“…This suggests enhanced activation of specific PAX target genes, 12 such as platelet-derived growth factor PDGF, 13 insuline-like growth factor 2 (IGF2), IGF-binding protein 5 (IGFBP5) or muscle-specific genes like Myogenin, MyoD and Six1. 14 Thus, continuous expression of aberrant fusion genes may inhibit terminal differentiation, maintain cells in a primitive state and induce continuous abnormal proliferation. 15 However, additional genetic changes have to occur to fully transform premalignant cells expressing oncogenic fusion transcripts.…”

mentioning

confidence: 99%

Profiling and functional annotation of mRNA gene expression in pediatric rhabdomyosarcoma and Ewing's sarcoma

Baer

Nees

Breit

et al. 2004

Intl Journal of Cancer

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Using Affymetrix oligonucleotide microarrays, we analyzed mRNA gene expression patterns of 12 primary pediatric rhabdomyosarcomas (RMS) and 11 Ewing's sarcomas (EWS), which belong to the small round blue cell tumors (SRBCTs). Diagnostic classification of these cancers is frequently complicated by the highly similar appearance in routine histology, and additional molecular markers could significantly improve tumor classification. A combination of three independent statistical approaches (t-test, SAM, k-nearest neighborhood analysis) resulted in 101 highly significant probe sets that clearly discriminate between EWS and RMS. We identified novel marker transcripts that have not been previously associated with either RMS or EWS yet, including CITED2, glypican 3 (GPC3), and cyclin D1 (CCND1). Expression levels for selected candidate genes were validated by quantitative real-time reverse-transcription PCR. Furthermore, to identify biologically meaningful trends, functional annotations were assigned to 946 genes differentially expressed between EWS and RMS (t-test). Genes involved in protein biosynthesis (n ‫؍‬ 28) and complex assembly (n ‫؍‬ 9), lipid metabolism (n ‫؍‬ 23), energy generation (n ‫؍‬ 22), and mRNA processing (n ‫؍‬ 11) were expressed significantly higher in EWS. Thus, functional annotation of tumor-specific genes reveals detailed insights into tumor biology and differentiation-specific expression patterns and gives important clues related to the possible cellular origin of these pediatric tumors. Small round blue cell tumors (SRBCTs) are frequently difficult to distinguish by standard histology or, sometimes, even by immunohistochemistry. Rhabdomyosarcoma (RMS) and Ewing's sarcomas (EWS) are common pediatric solid tumors that belong to this group that also includes neuroblastoma and Burkitt's lymphoma. However, the correct diagnosis of SRBCT tumors is essential since treatment regimens, response to therapy and prognosis may differ markedly. Therefore, molecular techniques are increasingly implemented for the diagnostic distinction of SRBCT tumors, including EWS and RMS. Progress in recent years includes the identification of characteristic tumor-specific chromosomal translocations, resulting in the expression of aberrant, oncogenic fusion proteins.RMS is the most common pediatric soft tissue sarcoma and can be histologically subdivided into the more prevalent embryonal (eRMS) and the more aggressive alveolar rhabdomyosarcoma (aRMS). ARMS have an unfavorable prognosis due to a tendency to early relapses and frequent failure of chemotherapy. This is reflected by 5-year survival rates ranging between 20 -50%. Most aRMS express PAX3-FKHR or PAX7-FKHR fusion proteins resulting from [t(2;13)(q35;q14)] or [t(1;13)(p36;q14)] translocations, respectively. 1-3 Although a frequently affected chromosomal locus in eRMS has been defined (11p15.5), specific gene(s) or a fusion transcript have not been identified. 4 Ewing's sarcomas (EWS) and the related, more differentiated peripheral neuroectodermal tumors (PNET) are...

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cDNA microarrays detect activation of a myogenic transcription program by thePAX3-FKHRfusion oncogene

Cited by 292 publications

References 35 publications

PAX-FKHR function as pangenes by simultaneously inducing and inhibiting myogenesis

PAX-FKHR function as pangenes by simultaneously inducing and inhibiting myogenesis

A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process

Profiling and functional annotation of mRNA gene expression in pediatric rhabdomyosarcoma and Ewing's sarcoma

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