Abstract
Wig-1 is a transcriptional target of the tumor suppressor p53. p53 is
activated by cellular stress and can induce a wide variety of responses.
Some like apoptosis follow upon severe damage, while milder damage
results in outcomes such as cell cycle arrest and DNA repair. Yet other
p53 functions rely on physiological p53 levels. p53 mainly exerts its
functions through inducing the transcription of target genes, hence in
order to understand the function of p53 one must understand the function
of these targets. Wig-1 was identified as a p53 target more than ten
years ago, and was found to be a double stranded RNA binding protein.
Apart from that, however, its function has remained elusive. In this work
we demonstrate that Wig-1 regulates mRNA stability through binding to
so-called AU-rich elements in 3 UTRs, and we identify p53 as well as N-
and c-Myc as its targets. We also report that Wig-1 knockout causes early
embryonic lethality in mice, probably due to dysregulation of Wig-1
targets such as Myc. Thus we show that p53, through Wig-1, can activate
Myc and possibly other prosurvival targets. This activation may represent
a way of facilitating for cells to recommence cycling after a repaired
damage. Simultaneously, increased Wig-1 sensitizes the cell to any
remaining damage by also stabilizing the p53 mRNA. In conclusion, we have
found that the p53 target Wig-1 regulates mRNA stability through AU-rich
elements. We propose a novel mechanism by which p53, through Wig-1, can
tweak the cell milieu toward survival.
