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Molecular and Cellular Biology, January 2004, p. 14-24, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.14-24.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Selective Estrogen Receptor Modulators 4-Hydroxytamoxifen and Raloxifene Impact the Stability and Function of SRC-1 and SRC-3 Coactivator Proteins

David M. Lonard, Sophia Y. Tsai, and Bert W. O'Malley*

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Received 21 May 2003/ Returned for modification 1 June 2003/ Accepted 24 September 2003

Proteasome-mediated protein degradation has been implicated in playing a role in nuclear receptor-mediated gene expression; inhibition of the proteasome impairs the transcriptional activity of estrogen receptor {alpha} (ER{alpha}) and most other nuclear receptors. This coincides with blockage of agonist-dependent degradation of the receptor and elevation of the steady-state levels of SRC family coactivators and CBP. Here, we examined the effects that different ER{alpha} ligands have on coactivator protein steady-state levels and demonstrate that the selective ER modulators (SERMs) 4-hydroxytamoxifen (4HT) and raloxifene are able to elevate SRC-1 and SRC-3 protein levels. Using the HeLa cell line, we show that this effect is ER{alpha} dependent. Consistent with the observed increase in coactivator protein levels, we were also able to observe an increase in the transcriptional activity of other nuclear receptors in SERM-treated cells. Information presented here demonstrates an unexpected consequence of SERM treatment, which could help further define the complex tissue responses to 4HT and raloxifene, and suggests that these ligands can have a broad biological action, stimulating the transcriptional activity of other nuclear receptors.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6205. Fax (713) 798-5599. E-mail: berto{at}bcm.tmc.edu.

Molecular and Cellular Biology, January 2004, p. 14-24, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.14-24.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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