Abstract
Wig-1 is a transcriptional target of the p53 tumor suppressor and encodes an mRNA stability-regulating protein. We show here that Wig-1 knockdown causes a dramatic inhibition of N-Myc expression and triggers differentiation in neuroblastoma cells carrying amplified N-Myc. Transient Wig-1 knockdown significantly delays development of N-Myc-driven tumors in mice. We also show that N-Myc expression is induced upon moderate p53-activating stress, suggesting a role of the p53-Wig-1-N-Myc axis in promoting cell cycle re-entry upon p53-induced cell cycle arrest and DNA repair. Moreover, our findings raise possibilities for the improved treatment of poor prognosis neuroblastomas that carry amplified N-Myc.
Highlights
The importance of p53-mediated tumor suppression is demonstrated by the high frequency of p53 mutations in human tumors
As the N-Myc mRNA is reported to be regulated through AREs18,19 we hypothesized that Wig-1 could affect N-Myc
We knocked down Wig-1 using two different siRNA oligos in two neuroblastoma cell lines carrying N-Myc amplification, SK-N-BE(2) and Kelly (Figures 1a and b), and detected a significant reduction in N-Myc protein levels in both cell lines with both siRNA oligos
Summary
The importance of p53-mediated tumor suppression is demonstrated by the high frequency of p53 mutations in human tumors (reviewed in Soussi and Wiman 3 see www-p53.iarc.fr and free.p53.fr). Wig-1 (for wild-type p53-induced gene 1) is a direct p53 target gene identified in mouse,[4] rat,[5] and human cells.[5,6,7] It is most strongly expressed in the nervous system, but is present in all cell types with enrichment in stem cells as compared with differentiated tissues.[8,9] Wig-1 is induced after cellular stress in a p53-dependent manner.[8] Wig-1 is a zinc finger protein that binds to double-stranded RNA,[10,11] and interacts with the RNA-binding proteins hnRNPA2/B1 and RNA Helicase A through RNA.[12] Wig-1 localizes mainly to the nucleus but can shuttle between the nucleus and the cytoplasm.[6,11,13,14] Wig-1 is highly conserved during evolution from amoeba to man.[8] We have recently shown that Wig-1 can bind to a U-rich element in the 30UTR of p53 mRNA, thereby stabilizing p53 mRNA by preventing its de-adenylation.[13] The U-rich region in the p53 30UTR is a subclass of the AU-rich elements (AREs) well known for their role in regulating mRNA stability and/or translation efficiency. N-Myc amplification is the most consistent marker of poor prognosis and aggressive disease in neuroblastoma.[20,22] N-Myc knockdown by siRNA in neuroblastoma cells carrying N-Myc amplification can induce differentiation,[23] and antisense strategies that target N-Myc inhibit mouse neuroblastoma tumorigenesis in vivo.[24]
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