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PMID: 9891052 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily.

Molecular and cellular biology ·Vol. 19 ·No. 2 ·1999-02-00 ·Pages 1182-9

Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, O'Malley BW

Abstract

In this study, we 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. Our 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. To correlate the E6-AP coactivator function and ubiquitin-protein ligase functions with the AS phenotype, we expressed mutant forms of E6-AP isolated from AS patients and assessed the ability of each of these mutant proteins to coactivate PR or provide ubiquitin-protein ligase activity. This analysis revealed that 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.

MeSH Terms
Angelman Syndrome/genetics,metabolism Base Sequence Binding Sites/genetics DNA Primers/genetics HeLa Cells Humans In Vitro Techniques Ligands Ligases/genetics,metabolism Mutation Phenotype Receptors, Estrogen/genetics,metabolism Receptors, Progesterone/genetics,metabolism Receptors, Steroid/genetics,metabolism Trans-Activators/genetics,metabolism Transcriptional Activation Ubiquitin-Protein Ligases
Chemicals
DNA Primers Ligands Receptors, Estrogen Receptors, Progesterone Receptors, Steroid Trans-Activators UBE3A protein, human Ubiquitin-Protein Ligases Ligases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Nawaz Z
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Lonard D M
Smith C L
Lev-Lehman E
Tsai S Y
Tsai M J
O'Malley B W
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.19.2.1182
Published
1999-02-00
Pages
1182-9
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC116047
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.19.2.1182 PMC Full Text View journal details
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