[Any way you splice it: Mdm2 at the crossroads of tumor surveillance]

Abstract

Mdm2 is the most important regulator of p53, the chief responder of various modes of cellular stress, including DNA damage and oncogenic insult. Many alternative and aberrant splice products of the Mdm2 gene product have been described, but relatively little is known about the origin, function, or consequence of these variants. Recently, a novel splice form of mdm2 was discovered which incorporates 108bp of intronic sequence into the mature Mdm2 mRNA. The additional sequence encodes in-frame stop codons, resulting in severely truncated mdm2 protein. Most intriguingly, this alternative splice form, termed Mdm2(+108), is acutely induced by the chemotherapeutic agents Adriamycin and Actinomycin D, but not other DNA damaging agents. The effect of Mdm2(+108) induction is a rapid and robust accumulation of p53, arguing that the function of this alternative splice event is to engage the p53 tumor surveillance pathway and restrain proliferation of cells damaged with these potently genotoxic compounds.