Abstract 1791: Tristetraprolin downregulates AHRR expression through mRNA destabilization.

Abstract

Background. The aryl hydrocarbon receptor repressor (AHRR) inhibits the transcription activity of the aryl hydrocarbon receptor (AHR) by competing for dimerization with the AHR nuclear translocator (ARNT) and subsequently binding to XRE. Interestingly, the AHRR has two AU-rich elements (AREs) in its 3’UTR which relates to the post-transcriptional regulation by ARE-binding proteins including Tristetraprolin (TTP), BRF1, HuR and so on. In previous study, we determined that TTP plays a critical role in the decaying of VEGF, LATS2, cIAP2, COX2 and Pim-1 through binding these AREs in 3’ UTR. Methodology/principal Findings. We investigated the post-transcriptional regulation of the AHRR expression by TTP. Our results show that the expression level of AHRR is inversely correlated with TTP expression in human breast cancer cell lines using the real-time PCR and western blot. The overexpression of TTP decreased the expression level of AHRR and inhibited the proliferation of MDA-MB435 human breast cancer cells. On the contrary, the treatment with a small interfering RNA against TTP increased the expression of AHRR mRNA and protein. AHRR mRNA contains two AREs within the 3’UTR and TTP destabilized a luciferase mRNA containing AHRR ARE. Moreover, RNA electrophoretic mobility shift assay revealed that TTP binds directly to the ARE of AHRR mRNA. Conclusions/Significance. These studies demonstrated that the TTP expression is inversely correlated with AHRR expression in several human breast cancer cell lines using the real-time PCR and western blot. We suggest that TTP acts as a negative regulator of the AHRR gene expression and it may have an effect on tumor development through inducing AHR activation and the expression of tumor suppressors containing XRE in human breast cancer cells. Citation Format: Hyun Hee Lee, Won Tae Kim, Dong Hee Kim, Sun-Hee Leem. Tristetraprolin downregulates AHRR expression through mRNA destabilization. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1791. doi:10.1158/1538-7445.AM2013-1791