Abstract
Abstract Aryl hydrocarbon receptor nuclear translocator (ARNT)/ hydroxia-inducible factor-1β (HIF-1β) is a basic helix-loop-helix Per/AhR/ARNT/Sim (bHLH-PAS) that forms dimeric transcriptional regulatory complexes with other bHLH-PAS proteins to regulate various biological pathways. Our previous report has shown that ARNT is also involved in epidermal growth factor (EGF)-induced COX-2 gene expression. By using pull-down and protein-DNA interaction assays, we herein report that ARNT is associated with transcription factors c-Jun/Sp1, and it regulates gene expression. We find that EGF stimulated the formation of the c-Jun/ARNT/Sp1 complex and the binding of the transcription protein complex to the Sp1 site of the gene promoter in a time-dependent manner. In addition, the promoter activity and the mRNA level of 12(S)-lipoxygenase upon EGF stimulation were inhibited by ARNT small interfering RNA (siRNA). Notably, ARNT cooperated with c-Jun to regulate gene expression. Although both c-Jun and ARNT have a transactivation domain, c-Jun was responsible for the EGF-induced transcriptional activation because a dominant negative c-Jun mutant, TAM-67, blocked ARNT-mediated 12(S) lipoxygenase expression, but not the binding of ARNT to the promoter. ARNT knockdown attenuated the association between c-Jun and Sp1 and the downregulation of gene expression. Furthermore, ARNT siRNA also inhibited other EGF-induced c-Jun/Sp1 mediated gene expression, such as p21WAF1/CIP1. Our results revealed a novel mechanism by which ARNT acts as a modulator to bridge the c-Jun/Sp1 interaction and plays a role in EGF-mediated gene expression under normoxic conditions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-19.
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