Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells
UMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2008-03-11Keywords
AnimalsApoptosis
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
Cell Biology
Metadata
Show full item recordAbstract
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.Source
Oncogene. 2008 Mar 6;27(11):1590-8. Epub 2007 Sep 10. Link to article on publisher's siteDOI
10.1038/sj.onc.1210788Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36011Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/sj.onc.1210788