Genetic ablation of the steroid receptor coactivator-ubiquitin ligase, E6-AP, results in tissue-selective steroid hormone resistance and defects in reproduction.
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.
Smith
Carolyn L
CL
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030-3498, USA. carolyns@bcm.tmc.edu
DeVera
Darryll G
DG
Lamb
Dolores J
DJ
Nawaz
Zafar
Z
Jiang
Yong-Hui
YH
Beaudet
Arthur L
AL
O'Malley
Bert W
BW
D000818:Animals; D004351:Drug Resistance; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D006128:Growth / Q000235:genetics / Q000502:physiology; D051548:Histone Acetyltransferases; D008025:Ligases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D011247:Pregnancy; D011467:Prostate / Q000187:drug effects / Q000254:growth & development; D011987:Receptors, Steroid / Q000502:physiology; D012098:Reproduction / Q000235:genetics / Q000502:physiology*; D013256:Steroids / Q000494:pharmacology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D044767:Ubiquitin-Protein Ligases
D011987:Receptors, Steroid; D013256:Steroids; D015534:Trans-Activators; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; C538867:Ncoa3 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D044767:Ubiquitin-Protein Ligases; D008025:Ligases