Wig-1 : a p53 target that regulates the mRNA of p53 and Myc – and more?

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.

List of scientific papers

I. Prahl M, Vilborg A, Palmberg C, Jörnvall H, Asker C, Wiman KG. (2008). "The p53 target protein Wig-1 binds hnRNP A2/B1 and RNA Helicase A via RNA" FEBS Lett 582: 2173-2177
https://pubmed.ncbi.nlm.nih.gov/18519039

II. Vilborg A, Glahder JA, Wilhelm MT, Bersani C, Corcoran M, Mahmoudi S, Rosenstierne M, Grandér D, Farnebo M, Norrild B, Wiman KG. (2009). "The p53 target Wig-1 regulates p53 mRNA stability through an AU-rich element." Proc Natl Acad Sci 106(37):15756-61 106: 15756-15761
https://pubmed.ncbi.nlm.nih.gov/

19805223

III. Vilborg A., Bersani C. and Wiman K.G (2010). "The p53 target Wig-1 regulates N-Myc mRNA levels and maintainins the de-differentiation phenotype of N-Myc amplified neuroblastoma cells, Manuscript," (Manuscript)

IV. Vilborg A., Rozell B., Bersani C., Wiman K.G. and Wilhelm M.T. (2010). "The p53 target gene Wig- 1 is essential for early embryonic development," (Manuscript)