Nucleolin links to arsenic-induced stabilization of GADD45α mRNA

The present study shows that arsenic induces GADD45 alpha (growth arrest and DNA damage inducible gene 45 alpha) mainly through post-transcriptional mechanism. Treatment of the human bronchial epithelial cell line, BEAS-2B, with arsenic(III) chloride (As3+) resulted in a significant increase in GADD45 alpha protein and mRNA. However, As3+ only exhibited a marginal effect on the transcription of the GADD45 alpha gene. The accumulation of GADD45 alpha mRNA is largely achieved by the stabilization of GADD45 alpha mRNA in the cellular response to As3+. As3+ is able to induce binding of mRNA stabilizing proteins, nucleolin and less potently, HuR, to the GADD45 alpha mRNA. Although As3+ was unable to affect the expression of nucleolin, treatment of the cells with As3+ resulted in re-distribution of nucleolin from nucleoli to nucleoplasm. Silencing of the nucleolin mRNA by RNA interference reversed As3+-induced stabilization of the GADD45 alpha mRNA and accumulation of the GADD45 alpha protein. Stabilization of GADD45 alpha mRNA, thus, represents a novel mechanism contributing to the production of GADD45 alpha and cell cycle arrest in response to As3+.