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Expression α Mechanism in Arsenic-Induced GADD 45 Dependent − Incorporation of an Internal Ribosome Entry Site

We have previously shown that trivalent arsenic (arsenite, As) is able to induce GADD45A expression in human bronchial epithelial cells through activation of c-Jun NH2terminal kinase and nucleolin-dependent mRNA stabilization. In the present report, we show that As is capable of inducing translation of the GADD45A protein through a cap-independent, or rather, an internal ribosome entry site (IRES)– dependent mechanism. In growth-arrested cells, As elevated the GADD45A protein level in a doseand time-dependent manner which did not correlate with the GADD45A mRNA expression. Pretreatment of the cells with rapamycin, an inhibitor for the cap-dependent translation machinery through the suppression of mTOR and p70S6 kinase, failed to affect the induction of the GADD45A protein induced by As. Sequence analysis revealed a potential IRES element in the 5¶-untranslated region of the GADD45A mRNA. This IRES element in the 5¶-untranslated region of the GADD45A mRNA is functional in mediating As-induced translation of the GADD45A protein in a dicistronic reporter gene activity assay. Immunoprecipitation and proteomic studies suggest that As impairs the assembly of the cap-dependent initiating complex for general protein translation but increases the association of human elongation factor 2 and human heterogeneous nuclear ribonucleoprotin with this complex. Thus, these results suggest that in growth-arrested cells, As is still capable of inducing GADD45A expression through an IRES-dependent translational regulation. [Cancer Res 2007;67(13):6146–54]