The EWS/TEC fusion protein encoded by the t(9;22) chromosomal translocation in human chondrosarcomas is a highly potent transcriptional activator

Labelle, Yves; Bussières, Johanne; Courjal, Frank; Goldring, Mary B.

doi:10.1038/sj.onc.1202675

Cited by 86 publications

(65 citation statements)

References 29 publications

(26 reference statements)

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“…Suppression of Nur77 expression inhibits the transformation phenotype of several cancer lines of different origins by promoting their apoptosis (Ke et al, 2004). The oncogenic potential of the Nur77 subfamily members is also suggested by the finding that Nor-1 (TEC) is involved in the t(9, 22) chromosomal translocation in extraskeletal myxoid chondrosarcoma (Labelle et al, 1995;Labelle et al, 1999). The resulting fusion protein, EWS/TEC, is potentially oncogenic, and it is much more active than the native receptor in transactivating target promoters, suggesting that transcriptional activation of Nor-1 is associated with oncogenicity.…”

Section: Nur77 As a Survival Factormentioning

confidence: 91%

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

2006

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The complex apoptotic functions of the p53 tumor suppressor are central to its antineoplastic activity in vivo. Conversely, p53 function is altered or attenuated in one way or another in the majority of human cancers. Besides its well-understood action as a transcriptional regulator of multiple apoptotic genes, p53 also exerts a direct pro-apoptotic role at the mitochondria by engaging in protein-protein interactions with anti-and pro-apoptotic Bcl2 family members, thereby executing the shortest known circuitry of p53 death signaling. Nur77, also known as TR3 or NGFI-B, is a unique transcription factor belonging to the orphan nuclear receptor superfamily. Even more extreme than p53, Nur77 can exert opposing biological activities of survival and death. Its activities are regulated by subcellular distribution, expression levels, protein modification and heterodimerization with retinoid X receptor. In cancer cells, Nur77 functions in the nucleus as an oncogenic survival factor, but becomes a potent killer when certain death stimuli induce its migration to mitochondria, where it binds to Bcl2 and conformationally converts it to a killer that triggers cytochrome c release and apoptosis. This review focuses on their unexpected transcription-independent pro-death programs at mitochondria and highlights the remarkable mechanistic similarities between them. Moreover, an accumulating body of evidence provides ample rationale to further investigate how these mitochondrial p53 and Nur77 pathways could become exploitable targets for new cancer therapeutics.

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Section: Nur77 As a Survival Factormentioning

confidence: 91%

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

2006

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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: 93%

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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“…The overexpression of oncogenes in human chondrosarcoma is a well established phenomenon. Among those reportedly expressed are c-met [23], amplified levels of c-myc [2,5] and fusion proteins encoded by the t(9;22) chromosomal translocation that are thought to have potent transcriptional activating properties [21]. As with c-fos, the specific roles played by these regulatory gene products in tumor growth, development, and metastasis remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Detection of c‐fos expression in benign and malignant musculoskeletal lesions

Weisstein

Majeska

Klein

et al. 2001

Journal Orthopaedic Research

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The proto-oncogene c-fos has been implicated in the development of both benign and malignant lesions of bone. Although c-fos expression in such lesions has been well studied in transgenic mouse models, less is known about its role in human musculoskeletal pathology. To clarify this relationship, we used in situ hybridization to localize c-fos m-RNA transcripts in 26 fibrous lesions (eight cases of extra-abdominal fibromatosis and six cases each of fibrous dysplasia, fibrosarcoma, and malignant fibrous histiocytoma of bone) as well as six chondrosarcomas and eight conventional high grade osteosarcomas. We found detectable levels of c-fos expression in tissues from each type of lesion tested. Moreover, all fibrous lesions consistently demonstrated high levels of expression in a majority of cells in each lesion. Chondrosarcomas and osteosarcomas exhibited more heterogeneity in c-fos expression than fibrous tissues. Three of six chondrosarcomas showed moderate expression of c-fos while only one of six was considered high. Similarly, only three of eight osteosarcomas had high expression of c-fos. These findings indicate that the expression of c-fos may be important in the development of a broad range of fibrous lesions as well as in bone and cartilaginous tumors. Additionally, this is the first report, to our knowledge, of detectable c-fos m-RNA in human chondrosarcoma.

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The EWS/TEC fusion protein encoded by the t(9;22) chromosomal translocation in human chondrosarcomas is a highly potent transcriptional activator

Cited by 86 publications

References 29 publications

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

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

Detection of c‐fos expression in benign and malignant musculoskeletal lesions

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