Overexpression of MDM2, due to enhanced translation, results in inactivation of wild-type p53 in Burkitt's lymphoma cells

Abstract

Numerous studies have indicated that inactivation of p53 is one of the essential requirements for the unrestrained growth of tumoral cells. When the status of the p53 gene was examined in various types of lymphoid malignancies, mutations in p53 have been predominantly detected in Burkitt's lymphoma (BL) cells, therefore suggesting that alteration of p53 could speci®cally contribute to the malignant phenotype of these tumoral cells. In addition to mutations, functional inactivation of p53 can also occur through interaction of the wild-type gene product with various viral or cellular proteins. The cellular MDM2 protein, for example, is able to inhibit p53 tumor suppressor function by concealing its transactivation domain. Mdm2 gene ampli®cation has been described in several types of sarcomas, resulting in overexpression of the MDM2 protein. In this study, we have examined the status of MDM2 and p53 in 20 BL cell lines. Four were found to contain wild-type p53 and to overexpress MDM2 protein. Within these BL cells, both molecules are physically associated since they can be co-precipitated and p53 is inactivated as cells neither arrest in G1 nor enter apoptosis following g-radiation. We also report that the high level of the MDM2 protein in BL cells is neither associated with an ampli®cation of the mdm2 gene nor with an elevated level of RNA or an increased protein stability, but is rather due to an enhanced translation ability of the mdm2 RNA. These results indicate that in certain BL cells, overexpression of MDM2 protein regulated at the posttranscriptional level, induces an escape from p53-controlled cell growth.

MYC oncogenes and human neoplastic disease

“…Indeed the studies cited above may actually underestimate the frequency with which functional inactivation of p53 occurs in BL. Recent work performed in cell lines (Capoulade et al, 1998) has provided evidence for overexpression of mdm2, a protein which is a known inhibitor of p53 function (Piette et al, 1997). This observation clearly deserves further investigation in primary tumors.…”

JAK2V617F negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms

“…An increased translation of MDM2 was described in Burkitt's lymphoma cells and in chronic myelogenous leukemia through interaction of an intercistronic region located in exon 2 of MDM2 mRNA with the La autoantigen (Capoulade et al, 1998;Trotta et al, 2003). This conserved RNA-binding phosphoprotein interacts with a large variety of ligands and displays several functions, including inhibition of exonucleolytic digestion of RNA polymerase III transcripts, regulation of the processing of 5 0 and 3 0 ends of pre-tRNA precursors, and RNA chaperoning.…”

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

“…Mdm2 protein is commonly overexpressed in hematologic malignancies due to increased transcription or translation rather than amplification (Capoulade et al, 1998). As many as half of all human and murine lymphomas overexpress Mdm2 protein, including lymphomas that have inactivated the tumor suppressor p53 or p14/p19 ARF (Watanabe et al, 1996;Eischen et al, 1999;Alt et al, 2003;Wilda et al, 2004;Ghobrial et al, 2005).…”