Nucleolin links to arsenic-induced stabilization of GADD45a mRNA

The present study shows that arsenic induces GADD45a (growth arrest and DNA damage inducible gene 45a) mainly through post-transcriptional mechanism. Treatment of the human bronchial epithelial cell line, BEAS-2B, with arsenic(III) chloride (As) resulted in a significant increase in GADD45a protein and mRNA. However, As only exhibited a marginal effect on the transcription of the GADD45a gene. The accumulation of GADD45a mRNA is largely achieved by the stabilization of GADD45a mRNA in the cellular response to As. As is able to induce binding of mRNA stabilizing proteins, nucleolin and less potently, HuR, to the GADD45a mRNA. Although As was unable to affect the expression of nucleolin, treatment of the cells with As resulted in re-distribution of nucleolin from nucleoli to nucleoplasm. Silencing of the nucleolin mRNA by RNA interference reversed As-induced stabilization of the GADD45a mRNA and accumulation of the GADD45a protein. Stabilization of GADD45a mRNA, thus, represents a novel mechanism contributing to the production of GADD45a and cell cycle arrest in response to As.