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

Zafar Nawaz, David M. Lonard, Carolyn L. Smith, Efrat Lev-Lehman, Sophia Y. Tsai, Ming Jer Tsai, Bert W. O'Malley

Research output: Contribution to journalArticle

315 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1182-1189
Number of pages8
JournalMolecular and Cellular Biology
Volume19
Issue number2
StatePublished - Feb 1 1999
Externally publishedYes

Fingerprint

Angelman Syndrome
Ubiquitin-Protein Ligases
Cytoplasmic and Nuclear Receptors
Proteins
Aptitude
Progesterone Receptors
Hormones
Phenotype
Inborn Genetic Diseases
Mutant Proteins
Ubiquitin
Nervous System Diseases
Human Activities
Intellectual Disability
Proteolysis
Seizures
Mothers
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Nawaz, Z., Lonard, D. M., Smith, C. L., Lev-Lehman, E., Tsai, S. Y., Tsai, M. J., & O'Malley, B. W. (1999). The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Molecular and Cellular Biology, 19(2), 1182-1189.

The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. / Nawaz, Zafar; Lonard, David M.; Smith, Carolyn L.; Lev-Lehman, Efrat; Tsai, Sophia Y.; Tsai, Ming Jer; O'Malley, Bert W.

In: Molecular and Cellular Biology, Vol. 19, No. 2, 01.02.1999, p. 1182-1189.

Research output: Contribution to journalArticle

Nawaz, Z, Lonard, DM, Smith, CL, Lev-Lehman, E, Tsai, SY, Tsai, MJ & O'Malley, BW 1999, 'The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily', Molecular and Cellular Biology, vol. 19, no. 2, pp. 1182-1189.
Nawaz, Zafar ; Lonard, David M. ; Smith, Carolyn L. ; Lev-Lehman, Efrat ; Tsai, Sophia Y. ; Tsai, Ming Jer ; O'Malley, Bert W. / The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. In: Molecular and Cellular Biology. 1999 ; Vol. 19, No. 2. pp. 1182-1189.
@article{d0067709c9c44965b56c860d600ce093,
title = "The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily",
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.",
author = "Zafar Nawaz and Lonard, {David M.} and Smith, {Carolyn L.} and Efrat Lev-Lehman and Tsai, {Sophia Y.} and Tsai, {Ming Jer} and O'Malley, {Bert W.}",
year = "1999",
month = "2",
day = "1",
language = "English",
volume = "19",
pages = "1182--1189",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "2",

}

TY - JOUR

T1 - The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily

AU - Nawaz, Zafar

AU - Lonard, David M.

AU - Smith, Carolyn L.

AU - Lev-Lehman, Efrat

AU - Tsai, Sophia Y.

AU - Tsai, Ming Jer

AU - O'Malley, Bert W.

PY - 1999/2/1

Y1 - 1999/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0032907106&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032907106&partnerID=8YFLogxK

M3 - Article

VL - 19

SP - 1182

EP - 1189

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 2

ER -