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

Wang P, Lushnikova T, Odvody J, Greiner TC, Jones SN, Eischen CM
Oncogene. 2008 27 (11): 1590-8

PMID: 17828300 · DOI:10.1038/sj.onc.1210788

Mdm2, a regulator of the p53 tumor suppressor, is frequently overexpressed in lymphomas, including lymphomas that have inactivated p53. However, the biological consequences of Mdm2 overexpression in lymphocytes are not fully resolved. Here, we report that increased expression of Mdm2 in B cells augmented proliferation and reduced susceptibility to p53-dependent apoptosis, which was due to inhibition of p53 and suppression of p21 expression. Notably, developing and mature B cells from Mdm2 transgenic mice had an increased frequency of chromosomal/chromatid breaks and/or aneuploidy. This Mdm2-mediated genome instability occurred at a similar frequency as that in B cells overexpressing the oncogene c-Myc, but the chromosomal instability was not further enhanced when Mdm2 and c-Myc were overexpressed together. Elevated Mdm2 expression alone increased the occurrence of B-cell transformation in vivo and cooperated with c-Myc overexpression, resulting in an acceleration of B-cell lymphomagenesis. In addition, the frequency of p53 mutations was reduced, but not eliminated, in lymphomas arising in Mdm2/Emu-myc double transgenic mice. Therefore, increased Mdm2 expression facilitated B-cell lymphomagenesis, in part, through regulation of p53 by altering B-cell proliferation and susceptibility to apoptosis, and by inducing chromosomal instability.

MeSH Terms (18)

Animals Apoptosis Blotting, Southern Blotting, Western Cell Survival Chromosomal Instability Female Humans Lymphoma, B-Cell Male Mice Mice, Transgenic Mutagenesis, Site-Directed Precursor Cells, B-Lymphoid Proto-Oncogene Proteins c-mdm2 Proto-Oncogene Proteins c-myc Survival Rate Tumor Suppressor Protein p53

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