Incorporation of an internal ribosome entry site-dependent mechanism in arsenic-induced GADD45α expression

Qingshan Chang, Deepak Bhatia, Yadong Zhang, Terry Meighan, Vince Castranova, Xianglin Shi, Fei Chen

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

We have previously shown that trivalent arsenic (arsenite, As3+) is able to induce GADD45α expression in human bronchial epithelial cells through activation of c-Jun NH2-terminal kinase and nucleolin-dependent mRNA stabilization. In the present report, we show that As3+ is capable of inducing translation of the GADD45α protein through a cap-independent, or rather, an internal ribosome entry site (IRES)-dependent mechanism. In growth-arrested cells, As3+ elevated the GADD45α protein level in a dose- and time-dependent manner which did not correlate with the GADD45α 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 GADD45α protein induced by As3+. Sequence analysis revealed a potential IRES element in the 5′-untranslated region of the GADD45α mRNA. This IRES element in the 5′-untranslated region of the GADD45α mRNA is functional in mediating As3+-induced translation of the GADD45α protein in a dicistronic reporter gene activity assay. Immunoprecipitation and proteomic studies suggest that As3+ 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, As3+ is still capable of inducing GADD45α expression through an IRES-dependent translational regulation.

Original languageEnglish
Pages (from-to)6146-6154
Number of pages9
JournalCancer Research
Volume67
Issue number13
DOIs
StatePublished - Jul 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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