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Submitted on March 10, 2004
Accepted on June 3, 2004
Department of Environmental Medicine, Center for Community Medicine, Jichi Medical School, Kawachi-gun, Tochigi 329-0498, Japan, School of Agriculture, Ibaraki University, Ami-machi, Ibaraki 300-0393, Japan, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka 545-8585, Japan and Forth Dept. of Internal medicine, Saitama Medical School, Iruma-gun, Saitama 350-0495, Japan, CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan
* To whom correspondence should be addressed. E-mail: ya{at}jichi.ac.jp.
The nucleo-cytoplasmic shuttling protein AUF1 is one of the RNA binding proteins that specifically bind adenylate-uridylate rich elements (ARE) in mRNA 3'-untranslated regions (UTRs), and acts as a regulator of ARE-mediated mRNA degradation in the cytoplasm. We previously reported that in the female rat uterus, the levels of specific AUF1 isoform mRNAs (p40/p45) were increased by 17
-estradiol (E2) treatment. Therefore, we examined the role of AUF1 in the regulation of E2-mediated mRNA turnover in the rat uterus. We identified ABIN2 and Ier2/pip92 mRNAs as candidate targets of AUF1 in the rat uterus. We found that AUF1 binding elements were present in the 3'-UTR of both mRNAs and that the 3'-UTRs functioned as mRNA turnover regulatory elements. In the OVX rat uterus, the nucleo-cytoplasmic localization of AUF1p40/p37 isoform proteins was regulated by E2. We also found that cytoplasmic AUF1-bound mRNA levels changed coincidentally with the cytoplasmic levels of AUF1p40/p37. Finally, we confirmed that the subcellular localization of AUF1p40 controlled the stability of target mRNAs in vitro, such that cytoplasmically-localized AUF1p40 led to marked mRNA stabilization, while nuclear-localized AUF1p40 stabilized target mRNA only slightly. These results suggested that E2-inducible ARE-containing gene transcripts are regulated at least in part via mRNA stabilization through the nucleo-cytoplasmic re-localization of AUF1.
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