Sign up for Table of Contents Alerts.
Cell Cycle is published 24 times a year.
Email this page
Print this page
Brief Report
Identification and characterization of a novel Mdm2 splice variant acutely induced by the chemotherapeutic agents Adriamycin and Actinomycin D
Nathan H. Lents, Leroy W. Wheeler, Joseph J. Baldassare and Brian David Dynlacht
volume 7 | issue 11
1 June 2008Pages: 1580 - 1586
Subscribe to this journal for $129/year
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 and the E3 ubiquitin ligase activity. 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 marked 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.
Authors
Nathan H. Lents
John Jay College of Criminal Justice; New York, NY
Leroy W. Wheeler
Saint Louis University School of Medicine; Saint Louis, MO
Joseph J. Baldassare
Saint Louis University School of Medicine; Saint Louis, MO
Brian David Dynlacht
New York University Medical Center; New York, NY