Opposite regulation of estrogen receptor-α and its variant ER-α36 by the Wilms' tumor suppressor WT1

Kang,Lianguo; Wang,Lei; Wang,Zhao-Yi

doi:10.3892/ol.2011.250

Opposite regulation of estrogen receptor-α and its variant ER-α36 by the Wilms' tumor suppressor WT1

Authors:
- Lianguo Kang
- Lei Wang
- Zhao-Yi Wang
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Affiliations: Department of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, NE 68178, USA
Published online on: January 21, 2011 https://doi.org/10.3892/ol.2011.250
Pages: 337-341

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Abstract

The genomic and non-genomic signaling pathways are well-known estrogen signaling pathways. The 66-kDa estrogen receptor-α (ER-α66) is a typical ligand-inducible transcription factor that mainly mediates genomic estrogen signaling. Recently, we identified and cloned a 36-kDa variant of ER-α66, known as ER-α36. This variant lacks intrinsic transcription activity and predominantly mediates non-genomic estrogen signaling. Thus, the expression of ER-α66 and ER-α36 should be dynamically regulated and carefully coordinated to maintain a balance between genomic and non-genomic estrogen signaling. However, the molecular mechanisms underlying this correlation remain poorly understood. The Wilms' tumor suppressor gene, wt1, encodes a zinc-finger protein WT1 that functions as a dual transcription regulator to activate or suppress gene transcription. High levels of WT1 expression are associated with breast cancer malignancy. In the present study, high-passage ER-positive breast cancer MCF7 cells were found to express ER-α66 and WT1 at higher levels and ER-α36 at a very low level. Using the small hairpin RNA method, stable MCF7 cells were established that expressed knocked-down levels of WT1. The cells expressed a reduced level of ER-α66 but an increased level of ER-α36, suggesting that WT1 regulates the expression of ER-α66 and ER-α36 oppositely. Further co-transfection assays showed that all isoforms of WT1 directly activated the promoter activity of the ER-α66 gene while suppressing ER-α36 promoter activity. Our results therefore indicate that WT1 is a dual transcription factor that regulates the promoter activity of ER-α66 and ER-α36 oppositely, implicating WT1 as one of the coordinators that orchestrate genomic and non-genomic estrogen signaling.

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