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Discovery and Characterization of a novel DNA damage‐induced splice variant of Mdm2
Author(s) -
Lents Nathan H,
Dynlacht Brian David
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.775.2
Subject(s) - mdm2 , dna damage , ubiquitin ligase , biology , microbiology and biotechnology , splice , ubiquitin , dna ligase , dna repair , rna splicing , dna , genetics , gene , rna
Mdm2, as the most important negative regulator of p53, plays an important homeostatic role in regulating cell division and the cellular response to DNA damage, oncogenic insult, and other forms of cellular stress. We discovered that the DNA damaging agent adriamycin (doxorubicin) induces a novel aberrantly spliced Mdm2 mRNA which incorporates 108bp of intronic sequence not normally found in the Mdm2 mature mRNA. Accordingly, we term this Mdm2 splice variant Mdm2 +108 . Importantly, this insertion introduces in‐frame nonsense codons, thus encoding a profoundly truncated mdm2 protein lacking the C‐terminal RING finger domain, E3 ubiquitin ligase activity, and p53‐binding site. A wide range of pharmacological testing revealed that Mdm2 +108 is induced, in mouse and rat cells, in specific response to Adriamycin and actinomycin D, but not other modes of DNA damage. Meanwhile, antibodies against the N‐terminal region of mdm2 reveal a >90% reduction in detectable mdm2 protein upon Adriamycin treatment, while p53 accumulates to strikingly high levels. We thus conclude that this alternative spicing of Mdm2 may be an important mechanism to facilitate massive accumulation of p53 in response to genotoxic agents.