Transcriptional activation of cathepsin D gene expression by growth factors

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

Research output: Contribution to journalArticle

32 Scopus citations

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
DOIs
StatePublished - Apr 2000
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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