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Identification and Characterization of Two Novel Splicing Isoforms of Human Estrogen-Related Receptor ß

Departments of Biochemistry (W.Z., J.-h.L., D.B.L.), Animal Sciences (Z.L., E.A., D.B.L.), and Child Health (D.B.L.), Dalton Cardiovascular Research Center and Department of Biomedical Sciences (J.W., S.M.H.), University of Missouri Center for Phytonutrient and Phytochemical Studies (W.Z., J.-h.L., D.B.L.), University of Missouri, Columbia, Missouri 65211

Address all correspondence and requests for reprints to: Dr. Dennis B. Lubahn, Room 110A ASRC, 920 East Campus Drive, University of Missouri, Columbia, Missouri 65211. E-mail: lubahnd{at}missouri.edu.

Context: Estrogen-related receptor ß (ERRß) was one of the first two orphan nuclear receptors reported and is believed to play important roles in estrogen-regulated pathways. Embryo lethality of ERRß-null mice indicated that ERRß is essential for embryo development.

Objective: Two novel splicing isoforms of human (h) ERRß, hERRß2-10 and short-form hERRß, were identified during the cloning of previously reported hERRß-hERRß2. We aim to investigate the functional differences of these three human ERRß-splicing isoforms.

Results and Conclusions: A genomic sequence comparison within and flanking the ERRß genes of eight species demonstrated that short-form hERRß lacks an F domain and is the matched homolog of mouse and rat ERRß proteins in humans. However, hERRß2-10 and the previously reported hERRß2 isoforms are primate specific. RT-PCR analysis showed that short-form hERRß has a wide distribution in the 24 of 27 human tissues and cell lines tested, whereas hERRß2 and hERRß2-10 were only expressed in testis and kidney. The three human ERRß-splicing isoforms have different transcriptional activities when measured on an estrogen response element-driven luciferase reporter in transfection assays. The localization of a nuclear localization signal of short-form hERRß was also determined. Interestingly, the F domain of hERRß2 alters the function of the nuclear localization signal. Therefore, the ERRß isoforms are likely to have diverse biological functions in vivo, and characterizing the three isoforms of ERRß will lead to an understanding of the multiple levels of gene regulation involved in steroid receptor-signaling pathways in humans and may provide novel therapeutic targets for human diseases.

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