MOLECULAR ABNORMALITIES OF MDM-2 IN HUMAN SARCOMAS

Abstract

MDM-2 is an oncoprotein that seems to function, at least in part, by interacting with the p53 protein and modulating its tumor-suppressing activity. The MDM-2 gene codes for p57, p74, p76, p85, and p90 proteins. Overexpression of only the p90 MDM-2 protein has been reported in sarcomas showing MDM-2 gene amplification. In addition, post-transcriptional mechanisms have been demonstrated to play a role in the expression of MDM-2 proteins. We investigated MDM-2 gene amplification, mRNA and protein levels in various cases of sarcomas. We found MDM-2 gene amplification in 12 (26%) of 46 cases of sarcoma: 11 of 13 cases of liposarcoma and 1 of 6 cases of malignant fibrous histiocytoma. The MDM-2 amplification correlated with the presence of elevated levels of mRNA and protein in the liposarcomas. In sarcomas other than liposarcomas, mRNA was overexpressed in 7 (30%) of 23 cases, without MDM-2 amplification. In 15 (62.5%) of 24 cases of sarcoma and in 1 case of lipoma the MDM-2 protein was overexpressed as shown by Western blot analysis. Interestingly, p57 not p90 was the most commonly overexpressed MDM-2 protein. These data indicate that the molecular abnormalities affecting MDM-2 expression in cases of sarcoma include transcriptional, post-transcriptional, and gene dosage (amplification) mechanisms. Furthermore, our findings suggest that MDM-2 p57 protein may be as important as p90 in the pathogenesis of human sarcomas.