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Xiaodong Li^1,*, Stephanie L Nott¹, Yanfang Huang¹, Russell Hilf¹, Robert A Bambara¹, Xing Qiu², Andrei Yakovlev^2,, Stephen Welle³

Departments of¹ Biochemistry and Biophysics² , Biostatistics and Computational Biology³ Medicine, University of Rochester Medical School, Rochester, New York 14642, USA

(Correspondence should be addressed to M Muyan who is now at 601 Elmwood Avenue, Box 712, Rochester, New York 14642, USA; Email: mesut_muyan{at}urmc.rochester.edu)

*X Li is now at HD Dimension Corporation, Princeton, New Jersey 08540, USA

A Yakovlev is now deceased

Estrogen hormone 17β-estradiol (E₂) is involved in the physiology and pathology of many tissues. E₂ information is conveyed by the transcription factors estrogen receptors (ER) and β that mediate a complex array of nuclear and non-nuclear events. The interaction of ER with specific DNA sequences, estrogen-responsive elements (EREs), constitutes a critical nuclear signaling pathway. In addition, E₂-ER regulates transcription through interactions with transfactors bound to their cognate regulatory elements on DNA, hence the ERE-independent signaling pathway. However, the relative importance of the ERE-independent pathway in E₂-ERβ signaling is unclear. To address this issue, we engineered an ERE-binding defective ERβ mutant (ERβ_EBD) by changing critical residues in the DNA-binding domain required for ERE binding. Biochemical and functional studies revealed that ERβ_EBD signaled exclusively through the ERE-independent pathway. Using the adenovirus infected ER-negative cancer cell models, we found that although E₂-ERβ_EBD regulated the expression of a number of genes identified by microarrays, it was ineffective in altering cellular proliferation, motility, and death in contrast to E₂-ERβ. Our results indicate that genomic responses from the ERE-independent pathway to E₂-ERβ are not sufficient to alter the cellular phenotype. These findings suggest that the ERE-dependent pathway is a required signaling route for E₂-ERβ to induce cellular responses.

This article has been cited by other articles:

				S. L. Nott, Y. Huang, X. Li, B. R. Fluharty, X. Qiu, W. V. Welshons, S. Yeh, and M. Muyan Genomic Responses from the Estrogen-responsive Element-dependent Signaling Pathway Mediated by Estrogen Receptor {alpha} Are Required to Elicit Cellular Alterations J. Biol. Chem., May 29, 2009; 284(22): 15277 - 15288. [Abstract] [Full Text] [PDF]