Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation

Labelle, Yves; Zucman, Jessica; Stenman, Göran; Kindblom, Lars‐Gunnar; Knight, Jennifer; Turc‐Carel, Claude; Dockhorn‐Dworniczak, Barbara; Mandahl, Nils; Desmaze, Chantal; Peter, Martine; Aurias, Alain; Delattre, Olivier; Thomas, Gilles

doi:10.1093/hmg/4.12.2219

Cited by 185 publications

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“…26,28 -30 In extraskeletal myxoid chondrosarcoma, however, exon 12 of EWS is the most common fusion point in EWS/CHN chimeras, though hybrid transcripts with EWS exon 7/CHN have been described. 31 In CCS, EWS exon 8 appears to be the preferred fusion point, but transcripts joining EWS exon 7 with ATF1 (types 2 and 4) may also be generated.…”

Section: Discussionmentioning

confidence: 99%

Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses

Panagopoulos

Mertens

Dębiec‐Rychter

et al. 2002

Intl Journal of Cancer

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137

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Clear cell sarcoma (CCS) is a rare malignant soft tissue tumor particularly associated with tendons and aponeuroses. The cytogenetic hallmark is the translocation t(12;22)(q13; q12) resulting in a chimeric EWS/ATF1 gene in which the 3 -terminal part of EWS at 22q is replaced by the 3 -terminal part of ATF1 at 12q. To date, only 13 cases of CCS have been analyzed for fusion genes at the transcription level, and there is no information about the breakpoints at the genomic level. In the present study, we describe the molecular genetic characteristics of CCS from 10 patients. Karyotypes were obtained from 10 cases, 7 of which showed the characteristic t(12;22). As an initial step in the characterization of the EWS/ATF1 and ATF1/EWS chimeras, we constructed an exon/ intron map of the ATF1 gene. The entire ATF1 gene spanned >40 kb and was composed of 7 exons. Intron 3, in which most of the genomic breakpoints occurred, was to a large extent (83%) composed of repetitive elements. RT-PCR amplified EWS/ATF1 cDNA fragments in all patients and ATF1/EWS cDNA fragments in 6 of 10 patients. Four types of EWS/ATF1 chimeric transcript, designated types 1-4, were identified. The most frequent chimeric transcript (type 1) was an inframe fusion of exon 8 of EWS with exon 4 of ATF1. This was the only chimeric transcript in 5 patients but found together with other variants in 3 tumors. The type 2 transcript of EWS/ATF1, an in-frame fusion of exon 7 of EWS with exon 5 of ATF1, was detected in 4 patients, as the only transcript in 1 case and together with other variants in 3 cases. An in-frame fusion of exon 10 of EWS with exon 5 of ATF1 (type 3) was found in 1 patient as the only transcript, and an out-of-frame fusion of EWS exon 7 with ATF1 exon 7 (type 4) was detected in 1 patient together with type 1 and type 2 transcripts. Sequencing of the amplified ATF1/EWS cDNA fragments showed in 5 patients that ATF1 exon 3 was fused with EWS exon 10, resulting in an out-of-frame chimeric transcript. In 1 case, nt 428 of ATF1 (exon 4) was fused with EWS exon 8; at the junction, there was an insertion of 4 nucleotides, also resulting in an out-of-frame transcript. Genomic extra long PCR and sequence analysis mapped the genomic breakpoints to introns 7, 8 and 9 of EWS and intron 3 and exon 4 of ATF1. While a simple end-to-end fusion was observed in 2 cases, additional nucleotides were found at the junctions in 2 other cases. In addition, topoisomerase I consensus sequences were found close to the junctions, suggesting that this enzyme may participate in the genesis of the EWS/ATF1 fusion.

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Section: Discussionmentioning

confidence: 99%

Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses

Panagopoulos

Mertens

Dębiec‐Rychter

et al. 2002

Intl Journal of Cancer

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137

119

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“…The mitogenic effect of Nur77 likely occurs in the nucleus as it requires Nur77 DNA-binding and transactivation (Kolluri et al, 2003). A chimeric protein involving Nur77 subfamily member Nor-1 from a chromosomal translocation in chondrosarcoma is a potent transcriptional activator, suggesting that Nur77 transcriptional activation may be oncogenic (Labelle et al, 1995(Labelle et al, , 1999. Consistently, Nur77 is one of the 17-gene-signature genes associated with metastasis of several primary solid tumors (Ramaswamy et al, 2003).…”

Section: Introductionmentioning

confidence: 94%

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

et al. 2006

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Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN)/ CD437 class. In this study, we investigated the molecular mechanism by which AHPN/CD437 analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces Nur77 nuclear export. Our results demonstrate that 3-Cl-AHPC effectively activated Jun N-terminal kinase (JNK), which phosphorylates Nur77. Inhibition of JNK activation by a JNK inhibitor suppressed 3-Cl-AHPC-induced Nur77 nuclear export and apoptosis. In addition, several JNK upstream activators, including the phorbol ester TPA, anisomycin and MAPK kinase kinase-1 (MEKK1), phosphorylated Nur77 and induced its nuclear export. However, Nur77 phosphorylation by JNK, although essential, was not sufficient for inducing Nur77 nuclear export. Induction of Nur77 nuclear export by MEKK1 required a prolonged MEKK1 activation and was attenuated by Akt activation. Expression of constitutively active Akt prevented MEKK1-induced Nur77 nuclear export. Conversely, transfection of dominant-negative Akt or treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor accelerated MEKK1-induced Nur77 nuclear export. Furthermore, mutation of an Akt phosphorylation residue Ser351 in Nur77 abolished the effect of Akt or the PI3-K inhibitor. Together, our results demonstrate that both activation of JNK and inhibition of Akt play a role in translocation of Nur77 from the nucleus to the cytoplasm.

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“…Fusions of EWS to other families of transcription factors have been observed in di erent types of tumors, including CHOP in myxoid liposarcoma (Panagopoulos et al, 1996), ATF-1 in malignant melanoma of soft parts (Zucman et al, 1993a;Fujimura et al, 1996), WT1 in intra-abdominal desmoplastic small round cell tumor (Ladanyi and Gerald, 1994) and to orphan nuclear receptors in myxoid chondrosarcoma (Labelle et al, 1995;Clark et al, 1996). TLS/FUS-CHOP and TLS/FUS-ERG chimeras have been described in myxoid liposarcoma (Rabbitts et al, 1993;Crozat et al, 1993) and acute myeloid leukemia (Panagopoulos et al, 1994;Ichikawa et al, 1994), respectively.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II

et al. 1998

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As a result of the t(11;22)(q24;q12) chromosomal translocation characterizing the Ewing family of tumors (ET), the amino terminal portion of EWS, an RNA binding protein of unknown function, is fused to the DNA-binding domain of the ets transcription factor Fli1. The hybrid EWS-Fli1 protein acts as a strong transcriptional activator and, in contrast to wildtype Fli1, is a potent transforming agent. Similar rearrangements involving EWS or the highly homologous TLS with various transcription factors have been found in several types of human tumors. Employing yeast twohybrid cloning we isolated the seventh largest subunit of human RNA polymerase II (hsRPB7) as a protein that speci®cally interacts with the amino terminus of EWS. This association was con®rmed by in vitro immunocoprecipitation. In nuclear extracts, hsRPB7 was found to copurify with EWS-Fli1 but not with Fli1. Overexpression of recombinant hsRPB7 speci®cally increased gene activation by EWS-chimeric transcription factors. Replacement of the EWS portion by hsRPB7 in the oncogenic fusion protein restored the transactivating potential of the chimera. Our results suggest that the interaction of the amino terminus of EWS with hsRPB7 contributes to the transactivation function of EWS-Fli1 and, since hsRPB7 has characteristics of a regulatory subunit of RNA polymerase II, may in¯uence promoter selectivity.

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Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation

Cited by 185 publications

References 0 publications

Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses

Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II

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