E6AP was initially identified as a cellular protein that mediates the in vitro association of the human papillomavirus E6
protein with p53 (OMIM 191170), leading to the ubiquitin-dependent degradation of p53. The UBE3A gene encodes a member of a family of functionally related proteins defined by a conserved C-terminal
350-amino acid 'hect' domain. Hect E3 proteins appear to be important in substrate recognition and in ubiquitin transfer.
Nawaz Z, et al reported that the Angelman syndrome-associated protein, E6-AP, is a coactivator
for the nuclear hormone receptor superfamily.
The authors found that the E6-associated protein (E6-AP/UBE3A) directly
interacts with and coactivates the transcriptional activity of the human progesterone
receptor (PR) in a hormone-dependent manner. E6-AP also coactivates the
hormone-dependent transcriptional activities of the other members of the nuclear
hormone receptor superfamily. Previously, it was shown that E6-AP serves the role of
a ubiquitin-protein ligase (E3) in the presence of the E6 protein from human
papillomavirus types 16 and 18. The present data show that the ubiquitin-protein ligase
function of E6-AP is dispensable for its ability to coactivate nuclear hormone
receptors, showing that E6-AP possesses two separable independent functions, as
both a coactivator and a ubiquitin-protein ligase. Disruption of the maternal copy of
E6-AP is correlated with Angelman syndrome (AS), a genetic neurological disorder
characterized by severe mental retardation, seizures, speech impairment, and other
symptoms. However, the exact mechanism by which the defective E6-AP gene causes
AS remains unknown. In the majority of the AS patients examined, the ubiquitin-protein ligase
function of E6-AP was defective whereas the coactivator function was intact. This
finding suggests that the AS phenotype results from a defect in the
ubiquitin-proteosome protein degradation pathway.
NCBI Summary:
This gene encodes an E3 ubiquitin-protein ligase, part of the ubiquitin protein degradation system. This imprinted gene is maternally expressed in brain and biallelically expressed in other tissues. Maternally inherited deletion of this gene causes Angelman Syndrome, characterized by severe motor and intellectual retardation, ataxia, hypotonia, epilepsy, absence of speech, and characteristic facies. The protein also interacts with the E6 protein of human papillomavirus types 16 and 18, resulting in ubiquitination and proteolysis of tumor protein p53. Alternative splicing of this gene results in three transcript variants encoding three isoforms with different N-termini. Additional transcript variants have been described, but their full length nature has not been determined.
General function
Transcription factor
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Cellular localization
Nuclear
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Ovarian function
Ovulation
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Expression regulated by
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Ovarian localization
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Carolyn L. Smith, et al 2002 reported that
Northern blot analysis of total RNA demonstrated that E6-AP mRNAs of approximately
4.5, 5.5, and 10 kb are expressed in the ovary, uterus, mammary gland, testis, and prostate.
Follicle stages
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Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: .
Carolyn L. Smith, et al 2002 reported that 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. 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.
The litter size
was 48% lower in knockout females than from wild-type controls (P < 0.001), indicating that E6-AP null female are
subfertile.
While ovaries from wild-type females revealed many corpora lutea and
developing follicles, E6-AP null ovaries were comparatively deficient in leuteinized cells and had fewer developing
follicles, a finding consistent with a phenotype of compromised oocyte production.