Role of insulin-like growth factor-I in regulating estrogen receptor-α gene expression

Adriana Stoica, Miguel Saceda, Amina Fakhro, Michael Joyner, Mary Beth Martin

Research output: Contribution to journalArticle

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Abstract

The role of insulin-like growth factor-I (IGF-I) in regulating estrogen receptor-α (ER-α) gene expression and activity was investigated in the human breast cancer cell line MCF-7. Treatment of cells with 40 ng/ml IGF-I resulted in a 60% decrease in ER-α protein concentration by 3 h, and the amount of ER-α remained suppressed for 24 h. A multiple-dose ligand-binding assay demonstrated that the decrease in ER-α protein corresponded to a similar decrease of 50% in estradiol-binding sites with no effect on the binding affinity of ER-α. The dissociation constant of the estradiol-ER-α complex in the absence of IGF-I (K(d)= 3 x 10-10 ± 0.5 x 10-10 M) was similar to the dissociation constant in the presence of IGF-I (K(d)= 6 X 10- 10 + 0.3 X 10-10 M). The decrease in ER-α protein concentration was paralleled by an 80% decrease in the steady-state amount of ER-α mRNA by 3 h. The IGF-I induced decrease in ER-α mRNA was due to the inhibition of ER- α gene transcription. When an 128-base pair ER-α-promoter-CAT construct was transfected into MCF-7 cells, treatment with IGF-I resulted in a 40% decrease in CAT activity, n contrast to the effects on ER-α, treatment with IGF-I induced two endogenous estrogen-regulated genes, progesterone receptor and pS2, by 4- and twofold, respectively. The pure antiestrogen IO-164,384 blocked this induction, suggesting that ER-α mediates the effects of IGF-I. Transient co-transfections of wild-type ER-α and an estrogen response element-CAT reporter into COS-1 cells demonstrated that IGF-I increased reporter gene activity. This effect was also blocked by ICI 164,384. Protein kinase A and phosphatidylinositol 3-kinase inhibitors blocked the IGF-I effects on ER-eα expression and activity, suggesting that these kinases may be involved in the cross-talk between the IGF-I and ER-α pathways. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)605-614
Number of pages10
JournalJournal of Cellular Biochemistry
Volume76
Issue number4
DOIs
Publication statusPublished - 2000
Externally publishedYes

Fingerprint

Insulin-Like Growth Factor I
Gene expression
Estrogen Receptors
Gene Expression
Genes
Estradiol
Estrogens
Cells
Phosphatidylinositol 3-Kinase
Estradiol Receptors
IGF Type 1 Receptor
Messenger RNA
Estrogen Receptor Modulators
COS Cells
MCF-7 Cells
Response Elements
Progesterone Receptors
Transcription
Cyclic AMP-Dependent Protein Kinases
Reporter Genes

Keywords

  • ER-α IGF-I effects
  • Gene expression

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Role of insulin-like growth factor-I in regulating estrogen receptor-α gene expression. / Stoica, Adriana; Saceda, Miguel; Fakhro, Amina; Joyner, Michael; Martin, Mary Beth.

In: Journal of Cellular Biochemistry, Vol. 76, No. 4, 2000, p. 605-614.

Research output: Contribution to journalArticle

Stoica, Adriana ; Saceda, Miguel ; Fakhro, Amina ; Joyner, Michael ; Martin, Mary Beth. / Role of insulin-like growth factor-I in regulating estrogen receptor-α gene expression. In: Journal of Cellular Biochemistry. 2000 ; Vol. 76, No. 4. pp. 605-614.
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