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UBIQUITIN-PROTEIN LIGASE E3A; UBE3A OKDB#: 1392
 Symbols: UBIQUITIN-PROTEIN LIGASE E3A; UBE3A Species: human
 Synonyms: HUMAN PAPILLOMAVIRUS E6-ASSOCIATED PROTEIN, E6AP|  Locus: 15q11-q13 in Homo sapiens


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General Comment 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
Comment
Cellular localization Nuclear
Comment
Ovarian function Ovulation
Comment
Expression regulated by
Comment
Ovarian localization
Comment 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
Comment
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.

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created: Jan. 4, 2002, 7:34 a.m. by: hsueh   email:
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last update: Aug. 15, 2003, 3:42 p.m. by: system    email:



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