""""""""We have continued to focus on the role of insulin-like growth factors (IGF's) and tumor specific translocations in the pathogenesis of pediatric sarcomas, specifically rhabdomyosarcomas (RMS), Ewing's sarcomas/PNET (Ewing's family of tumors EFT), and osteogenic sarcomas (OS). We have recently confirmed that the fusion protein PAX3-FKHR generated by the tumor specific translocation of alveolar RMS leads to overexpression of IGF2 and an IGF binding protein (IGFBP-5) critical for IGF signaling. Ongoing work seeks to identify the mechanism for this increased expression in PAX3-FKHR expressing cells. We have demonstrated that loss of imprinting (LOI) of IGF2 occurs uniformly in RMS and occasionally in EFT and have recently completed a study of the methylation patterns in the IGF2/H19 locus to determine whether this contributes to LOI. We have found that biallelic expression of IGFII found in human CNS tissue is associated with hypermethylation of the H19 region as has been seen in normal human liver with biallelic expression. In contrast, biallelic expression of IGFII in RMS is not associated with alterations in H19 methylation; suggesting different mechanisms contribute to LOI in tumors compared to normal tissue. We have demonstrated that wild-type p53 inhibits transcription from the P3 and P4 promoters of IGF2 by distinct mechanisms and mutant forms of p53 (commonly found in RMS) appear to have lost this activity potentially contributing to overexpression of IGF2 in these tumors. . We have utilized C2 myoblasts overexpressing IGFII to study the role of IGFII expression in cell cycle regulation. We have found that cells overexpressing IGFII have a markedly diminished G1 checkpoint following g irradiation despite induction of normal p53 and p21 levels. We have also shown that the transcription factor, AP-2, increases transcription of IGFII, and furthermore that AP-2 is overexpressed in RMS tumors with high IGFII expression. We are continuing our studies on murine osteosarcoma cell lines and have developed subclones of cells which form spontaneous metastases, and are currently using this model to identify critical genetic events leading to metastatic behavior. We have also begun experiments in dogs with spontaneous osteosarcoma to determine whether blocking the growth hormone-IGF-I axis may enhance the effect of chemotherapy by increasing apoptotic cell death.""""""""
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