Transcriptional activation of cathepsin D gene expression by growth factors

F. Wang, R. Duan, John Chirgwin, S. H. Safe

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Insulin-like growth factor-I (IGF-I), transforming growth factor α (TGFα) and epidermal growth factor (EGF) induced cathepsin D gene expression and reporter gene activity in MCF-7 human breast cancer cells transiently transfected with a construct (pCD1) containing a -2576 to -124 cathepsin D gene promoter insert. In contrast, IGF-I, but not TGFα or EGF, induced reporter gene activity in cells cotransfected with wild-type estrogen receptor (ER) expression plasmid and a construct (pCD2) containing estrogen- responsive downstream elements from -208 to -101. Promoter deletion and mutational analysis experiments identified four GC-rich sites and an imperfect palindromic estrogen responsive element required for IGF-I activation of the ER (ligand-independent). Subsequent studies with the mitogen-activated protein kinase (MAPK) inhibitor, PD98059, and a serine118-ER mutant confirmed the role of the MAPK pathway for IGF-I activation of the ER in MCF-7 cells. Thus, growth factor activation of ER can mediate transactivation vs ER/Sp1 binding to GC-rich sites and represents a novel pathway for ligand-independent ER action. The divergent pathways for IGF-I and TGFα/EGF activation of the ER observed in MCF-7 cells contrast with previous data indicating that pathways for growth factor activation of the ER are dependent on the gene and/or gene promoter and on cell context.

Original languageEnglish (US)
Pages (from-to)193-202
Number of pages10
JournalJournal of Molecular Endocrinology
Volume24
Issue number2
StatePublished - Apr 2000
Externally publishedYes

Fingerprint

Cathepsin D
Estrogen Receptors
Transcriptional Activation
Intercellular Signaling Peptides and Proteins
Gene Expression
Insulin-Like Growth Factor I
Transforming Growth Factors
Epidermal Growth Factor
MCF-7 Cells
Mitogen-Activated Protein Kinases
Reporter Genes
Estrogens
Genes
Ligands
Protein Kinase Inhibitors
Plasmids
Breast Neoplasms

ASJC Scopus subject areas

  • Endocrinology

Cite this

Transcriptional activation of cathepsin D gene expression by growth factors. / Wang, F.; Duan, R.; Chirgwin, John; Safe, S. H.

In: Journal of Molecular Endocrinology, Vol. 24, No. 2, 04.2000, p. 193-202.

Research output: Contribution to journalArticle

@article{a47e8f0883e64d4ba9e5c72e258077d5,
title = "Transcriptional activation of cathepsin D gene expression by growth factors",
abstract = "Insulin-like growth factor-I (IGF-I), transforming growth factor α (TGFα) and epidermal growth factor (EGF) induced cathepsin D gene expression and reporter gene activity in MCF-7 human breast cancer cells transiently transfected with a construct (pCD1) containing a -2576 to -124 cathepsin D gene promoter insert. In contrast, IGF-I, but not TGFα or EGF, induced reporter gene activity in cells cotransfected with wild-type estrogen receptor (ER) expression plasmid and a construct (pCD2) containing estrogen- responsive downstream elements from -208 to -101. Promoter deletion and mutational analysis experiments identified four GC-rich sites and an imperfect palindromic estrogen responsive element required for IGF-I activation of the ER (ligand-independent). Subsequent studies with the mitogen-activated protein kinase (MAPK) inhibitor, PD98059, and a serine118-ER mutant confirmed the role of the MAPK pathway for IGF-I activation of the ER in MCF-7 cells. Thus, growth factor activation of ER can mediate transactivation vs ER/Sp1 binding to GC-rich sites and represents a novel pathway for ligand-independent ER action. The divergent pathways for IGF-I and TGFα/EGF activation of the ER observed in MCF-7 cells contrast with previous data indicating that pathways for growth factor activation of the ER are dependent on the gene and/or gene promoter and on cell context.",
author = "F. Wang and R. Duan and John Chirgwin and Safe, {S. H.}",
year = "2000",
month = "4",
language = "English (US)",
volume = "24",
pages = "193--202",
journal = "Journal of Molecular Endocrinology",
issn = "0952-5041",
publisher = "Society for Endocrinology",
number = "2",

}

TY - JOUR

T1 - Transcriptional activation of cathepsin D gene expression by growth factors

AU - Wang, F.

AU - Duan, R.

AU - Chirgwin, John

AU - Safe, S. H.

PY - 2000/4

Y1 - 2000/4

N2 - Insulin-like growth factor-I (IGF-I), transforming growth factor α (TGFα) and epidermal growth factor (EGF) induced cathepsin D gene expression and reporter gene activity in MCF-7 human breast cancer cells transiently transfected with a construct (pCD1) containing a -2576 to -124 cathepsin D gene promoter insert. In contrast, IGF-I, but not TGFα or EGF, induced reporter gene activity in cells cotransfected with wild-type estrogen receptor (ER) expression plasmid and a construct (pCD2) containing estrogen- responsive downstream elements from -208 to -101. Promoter deletion and mutational analysis experiments identified four GC-rich sites and an imperfect palindromic estrogen responsive element required for IGF-I activation of the ER (ligand-independent). Subsequent studies with the mitogen-activated protein kinase (MAPK) inhibitor, PD98059, and a serine118-ER mutant confirmed the role of the MAPK pathway for IGF-I activation of the ER in MCF-7 cells. Thus, growth factor activation of ER can mediate transactivation vs ER/Sp1 binding to GC-rich sites and represents a novel pathway for ligand-independent ER action. The divergent pathways for IGF-I and TGFα/EGF activation of the ER observed in MCF-7 cells contrast with previous data indicating that pathways for growth factor activation of the ER are dependent on the gene and/or gene promoter and on cell context.

AB - Insulin-like growth factor-I (IGF-I), transforming growth factor α (TGFα) and epidermal growth factor (EGF) induced cathepsin D gene expression and reporter gene activity in MCF-7 human breast cancer cells transiently transfected with a construct (pCD1) containing a -2576 to -124 cathepsin D gene promoter insert. In contrast, IGF-I, but not TGFα or EGF, induced reporter gene activity in cells cotransfected with wild-type estrogen receptor (ER) expression plasmid and a construct (pCD2) containing estrogen- responsive downstream elements from -208 to -101. Promoter deletion and mutational analysis experiments identified four GC-rich sites and an imperfect palindromic estrogen responsive element required for IGF-I activation of the ER (ligand-independent). Subsequent studies with the mitogen-activated protein kinase (MAPK) inhibitor, PD98059, and a serine118-ER mutant confirmed the role of the MAPK pathway for IGF-I activation of the ER in MCF-7 cells. Thus, growth factor activation of ER can mediate transactivation vs ER/Sp1 binding to GC-rich sites and represents a novel pathway for ligand-independent ER action. The divergent pathways for IGF-I and TGFα/EGF activation of the ER observed in MCF-7 cells contrast with previous data indicating that pathways for growth factor activation of the ER are dependent on the gene and/or gene promoter and on cell context.

UR - http://www.scopus.com/inward/record.url?scp=0034126114&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034126114&partnerID=8YFLogxK

M3 - Article

C2 - 10750020

AN - SCOPUS:0034126114

VL - 24

SP - 193

EP - 202

JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

SN - 0952-5041

IS - 2

ER -