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Endocrinology Vol. 142, No. 4 1546-1553
Copyright © 2001 by The Endocrine Society

ARTICLES

Requirement of Sp1 and Estrogen Receptor {alpha} Interaction in 17ß-Estradiol-Mediated Transcriptional Activation of the Low Density Lipoprotein Receptor Gene Expression1

Cong Li, Michael R. Briggs, Thomas E. Ahlborn, Fredric B. Kraemer and Jingwen Liu

Veterans Affairs Palo Alto Health Care System (C.L., T.E.A., F.B.K., J.L.), Palo Alto, California 94304; Pharmacia Corp. (M.R.B.), St. Louis, Missouri 63017

Address all correspondence and requests for reprints to: Jingwen Liu, Ph.D. (154P), Vetarans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304.

Estrogen is one of the most important physiological regulators of low density lipoprotein receptor (LDLR) expression. Despite many studies conducted in animals and humans showing increased expressions of LDLR messenger RNA by hormone treatment, the molecular basis of the effect of estrogen on LDLR transcription has not been clearly elucidated. By using HepG2 cells that transiently express functional estrogen receptor {alpha} (ER{alpha}) and LDLR promoter constructs, we show that the specific interaction of ER{alpha} with the transcription factor Sp1 bound to the LDLR promoter is responsible for the activation of LDLR transcription by estrogen. We demonstrate that 1) mutations to abrogate the binding of Sp1 to its recognition sequences present in repeat 1 and repeat 3 elements of the LDLR promoter completely abolish the ER{alpha}-mediated activation of the LDLR promoter activity; 2) mutations that abolish the selective DNA-binding activity or inactivate the C-terminal transcription activation function (AF2) of ER{alpha} had no effect on the ability of ER{alpha} to activate LDLR transcription; however, transcriptional activation was completely lost by deletion of the N-terminal transcription activation region (AF1); 3) a subregion of AF1 (amino acids 67–139) was further identified to be important for ER{alpha} to activate the LDLR promoter; and 4) ER{alpha} enhanced the formation of Sp1-repeat 3 DNA complexes. We also show that mutation at the sterol-responsive element-1 site diminishes the activity of ER{alpha} on LDLR transcription, thereby suggesting that the sterol-responsive element-1-binding protein may interact with the Sp1-ER{alpha} complex to trans-activate LDLR gene transcription. This study for the first time provides a molecular basis for an understanding of the regulation of LDLR transcription by estrogens.




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