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Functions of EWS/ETS proteins

Neuroblastoma metastases in bones, with a criticism of Ewing ’ s endothelioma H.C. Colville and R.A. Willis Am J Pathol 1933; 9:421. Functions of EWS/ETS proteins.

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Functions of EWS/ETS proteins

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  1. Neuroblastoma metastases in bones, with a criticism of Ewing’s endotheliomaH.C. Colville andR.A. WillisAm J Pathol 1933; 9:421

  2. Functions of EWS/ETS proteins • Owing to the combined action of the EWS transcriptional activator and the FLI1 DNA-binding domain, they function as either aberrant transcription factors or potent repressors, or by altering RNA processing • EWS/ETS proteins also require the collaboration of additional proteins to perform their functions (AP-1, Fos-Jun, RNA helicase-A,..) • Additionally, EWS/FLI1 engages in post-transcriptional processes

  3. EWS/ETS Targets • EWS/FLI1 controls different routes of tumor development, maintenance, and progression in ES: • cell proliferation and survival (activation of targets IGF1, MYC, NKX2.2, TOPK) • escape from growth inhibition, senescence, and apoptosis (inhibition of p21, p57kip, TGFBR2, IGFBP3) • up-regulation of critical genes involved in neural tube and neural crest development (NKX2.2, CCK)

  4. Histogenesis • Endothelial cell (Ewing J) • Primitive haematopoietic cell (Roome NW & Delaney PA, 1932) • Primitive multipotent mesenchymal cell(Dickman PS et al, 1982) • Neuroectodermal cell (Lipinski M, 1986; Cavazzana AO et al, 1987)

  5. Which Cells Originate ES? • Crucial issue for discovering the mechanisms involved in the genesis of EFT, and for the identification of reliable molecular markers and possible therapeutic targets • The cellular context contributes to the phenotype, because the introduction of EWS/ETS fusions into different cellular models results in diverse outcomes ranging from the induction of cell cycle arrest, or apoptosis, to dedifferentiation • This suggests that EWS/FLI1 is a potent differentiation factor that blocks a preexisting commitment, at the same time imposing neural differentiation

  6. Which Cells Originate ES? • The expression of neural markers in EFT points to either a potential mesenchymal or a neuroectodermal origin • The EWS/FLI1 fusion protein can transform primary bone marrow-derived mesenchymal cells to form ES-like tumors in mice • EWS/FLI1 induces murine MSC transformation even in the absence of other prooncogenic events, suggesting that its generation would be the initiating event in EFT pathogenesis • However, the induction of EWS/FLI1 does not transform human MSC, suggesting the involvement of additional alterations

  7. Primary Malignant Bone Tumours Frequency and Percentage Distribution (4148 Cases) • Osteosarcoma 1718 (41.4%) • Chondrosarcoma 1049 (25.2%) • Ewing’s Sarcoma 512 (12.3%) • Chordoma 356 (8.5%) • Fibrosarcoma 255 (6.1%) • Angiosarcoma 93 (2.2%) • MFH 83 (2.0%) Dahlin’s Bone Tumors, Fifth Ed. 1996

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