Distinct roles for AF-1 and -2 of ER-alpha in regulation of MMP-13 promoter activity

Yamini Achari; Ting Lu; Benita S. Katzenellenbogen; David A. Hart

doi:10.1016/j.bbadis.2009.01.002

Distinct roles for AF-1 and -2 of ER-alpha in regulation of MMP-13 promoter activity

Yamini Achari, Ting Lu, Benita S. Katzenellenbogen, David A. Hart

Molecular and Integrative Physiology

Research output: Contribution to journal › Article › peer-review

Abstract

Previous studies have indicated that ER-α can influence the activity of the MMP-13 promoter. ER-α activity is mediated by two separate transcriptional activation domains (AF-1 and AF-2). The present study focused on analyzing the roles of these domains on the activation of the MMP-13 promoter. Transfection of synoviocytes with an ER-α construct lacking the C-terminus AF-2 domain led to significant elevation in MMP-13 promoter activity compared to wild type ER-α. Progressive deletions in the N-terminal AF-1 domain led to significant losses in MMP-13 promoter activity. MMP-13 promoter mutagenesis indicated that an AP-1 regulatory site was essential for ER-α mutant activity. Thus, both AF-1 and AF-2 domains of ER-α are required for regulation of MMP-13 promoter activity. As ER variants and ER related proteins have been implicated in bone and joint disorders, these findings provide understanding of the possible role of ER variants in the development of such conditions.

Original language	English (US)
Pages (from-to)	211-220
Number of pages	10
Journal	Biochimica et Biophysica Acta - Molecular Basis of Disease
Volume	1792
Issue number	3
DOIs	https://doi.org/10.1016/j.bbadis.2009.01.002
State	Published - Mar 2009

Keywords

AF-1
AF-2
AP-1 Site
ER-α mutant
Gene regulation
MMP-13

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology

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title = "Distinct roles for AF-1 and -2 of ER-alpha in regulation of MMP-13 promoter activity",

abstract = "Previous studies have indicated that ER-α can influence the activity of the MMP-13 promoter. ER-α activity is mediated by two separate transcriptional activation domains (AF-1 and AF-2). The present study focused on analyzing the roles of these domains on the activation of the MMP-13 promoter. Transfection of synoviocytes with an ER-α construct lacking the C-terminus AF-2 domain led to significant elevation in MMP-13 promoter activity compared to wild type ER-α. Progressive deletions in the N-terminal AF-1 domain led to significant losses in MMP-13 promoter activity. MMP-13 promoter mutagenesis indicated that an AP-1 regulatory site was essential for ER-α mutant activity. Thus, both AF-1 and AF-2 domains of ER-α are required for regulation of MMP-13 promoter activity. As ER variants and ER related proteins have been implicated in bone and joint disorders, these findings provide understanding of the possible role of ER variants in the development of such conditions.",

keywords = "AF-1, AF-2, AP-1 Site, ER-α mutant, Gene regulation, MMP-13",

author = "Yamini Achari and Ting Lu and Katzenellenbogen, {Benita S.} and Hart, {David A.}",

note = "Funding Information: These studies were supported by grants from the Institute for Gender and Health of CIHR, and The Arthritis Society (DAH), and NIH grant NIHCA18119 to BSK. DAH is the Calgary Foundation — Grace Glaum Professor in Arthritis Research. The assistance of Ms. Carol Reno with the RT-PCR experiments is gratefully acknowledged. ",

year = "2009",

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doi = "10.1016/j.bbadis.2009.01.002",

language = "English (US)",

volume = "1792",

pages = "211--220",

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AU - Hart, David A.

N1 - Funding Information: These studies were supported by grants from the Institute for Gender and Health of CIHR, and The Arthritis Society (DAH), and NIH grant NIHCA18119 to BSK. DAH is the Calgary Foundation — Grace Glaum Professor in Arthritis Research. The assistance of Ms. Carol Reno with the RT-PCR experiments is gratefully acknowledged.

PY - 2009/3

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N2 - Previous studies have indicated that ER-α can influence the activity of the MMP-13 promoter. ER-α activity is mediated by two separate transcriptional activation domains (AF-1 and AF-2). The present study focused on analyzing the roles of these domains on the activation of the MMP-13 promoter. Transfection of synoviocytes with an ER-α construct lacking the C-terminus AF-2 domain led to significant elevation in MMP-13 promoter activity compared to wild type ER-α. Progressive deletions in the N-terminal AF-1 domain led to significant losses in MMP-13 promoter activity. MMP-13 promoter mutagenesis indicated that an AP-1 regulatory site was essential for ER-α mutant activity. Thus, both AF-1 and AF-2 domains of ER-α are required for regulation of MMP-13 promoter activity. As ER variants and ER related proteins have been implicated in bone and joint disorders, these findings provide understanding of the possible role of ER variants in the development of such conditions.

AB - Previous studies have indicated that ER-α can influence the activity of the MMP-13 promoter. ER-α activity is mediated by two separate transcriptional activation domains (AF-1 and AF-2). The present study focused on analyzing the roles of these domains on the activation of the MMP-13 promoter. Transfection of synoviocytes with an ER-α construct lacking the C-terminus AF-2 domain led to significant elevation in MMP-13 promoter activity compared to wild type ER-α. Progressive deletions in the N-terminal AF-1 domain led to significant losses in MMP-13 promoter activity. MMP-13 promoter mutagenesis indicated that an AP-1 regulatory site was essential for ER-α mutant activity. Thus, both AF-1 and AF-2 domains of ER-α are required for regulation of MMP-13 promoter activity. As ER variants and ER related proteins have been implicated in bone and joint disorders, these findings provide understanding of the possible role of ER variants in the development of such conditions.

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Distinct roles for AF-1 and -2 of ER-alpha in regulation of MMP-13 promoter activity

Abstract

Keywords

ASJC Scopus subject areas

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