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Molecular and Cellular Biology, January 2002, p. 525-535, Vol. 22, No. 2
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.2.525-535.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Genetic Ablation of the Steroid Receptor Coactivator-Ubiquitin Ligase, E6-AP, Results in Tissue-Selective Steroid Hormone Resistance and Defects in Reproduction

Carolyn L. Smith,1* Darryll G. DeVera,1 Dolores J. Lamb,1,2 Zafar Nawaz,1 Yong-Hui Jiang,3 Arthur L. Beaudet,3 and Bert W. O’Malley1

Department of Molecular and Cellular Biology,1 Scott Department of Urology,2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030-34983

Received 13 April 2001/ Returned for modification 6 June 2001/ Accepted 5 October 2001

The E6-associated protein (E6-AP), although originally identified as a ubiquitin ligase, has recently been shown to function as a coactivator of steroid receptor-dependent gene expression in in vitro assays. In order to determine whether E6-AP acts as a coactivator in vivo, physiological parameters associated with male and female sex steroid action were assessed in the E6-AP null mouse. Gonadal size was reduced in E6-AP null male and female mice in comparison to wild-type controls in conjunction with reduced fertility in both genders. Consistent with this observation, defects in sperm production and function, as well as ovulation were observed. In comparison to wild-type controls, induction of prostate gland growth induced by testosterone and uterine growth by estradiol were significantly reduced. In contrast, estrogen and progesterone-stimulated growth of virgin mammary gland was not compromised by E6-AP ablation despite E6-AP expression in this tissue. This latter finding contrasts with the impaired estrogen and progesterone-induced mammary gland development observed previously for steroid receptor coactivator type 1 (SRC-1) and SRC-3 female knockout mice. Taken together, these results are consistent with a role for E6-AP in mediating a subset of steroid hormone actions in vivo. Nevertheless, differences observed between SRC and E6-AP knockout phenotypes indicate that these two families of steroid receptor coactivators are not functionally equivalent and supports the hypothesis that coactivators contribute to tissue-specific steroid hormone action.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6235. Fax: (713) 790-1275. E-mail: carolyns{at}bcm.tmc.edu.

Molecular and Cellular Biology, January 2002, p. 525-535, Vol. 22, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.2.525-535.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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