A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I

Mary Beth Martin, Thomas F. Franke, Gerald E. Stoica, Pierre Chambon, Benita S. Katzenellenbogen, Bogdan A. Stoica, Michael S. McLemore, Susan E. Olivo, Adriana Stoica

Research output: Contribution to journalArticle

Abstract

This study examines whether the serine/threonine protein kinase, Akt, is involved in the cross-talk between epidermal growth factor (EGF) and insulin-related growth factor I (IGF-I) receptors and ER-α. Treatment of MCF-7 cells with either EGF or IGF-I resulted in a rapid phosphorylation of Akt and a 14- to 16-fold increase in Akt activity, respectively. Akt activation was blocked by inhibitors of phosphatidylinositol 3-kinase, but not by an inhibitor of the ribosomal protein kinase p70S6K. Stable transfection of cells with a dominant negative Akt mutant blocked the effects of EGF and IGF-I on ER-α expression and activity, whereas stable transfection of cells with a constitutively active Akt mutant mimicked the effects of EGF and IGF-I. In the latter cells, there was a decrease in the amount of ER-α protein and messenger RNA (70-80%) and an increase in the amount of progesterone receptor protein, messenger RNA (4- to 9- and by 3.5- to 7-fold, respectively) and pS2 (3- to 5-fold). Coexpression of wild-type ER-α and the dominant negative Akt mutant in COS-1 cells also blocked the growth factor-stimulated activation of ER-α, but coexpression of the wild-type receptor with the constitutively active Akt mutant increased ER-α activity. Receptor activation was blocked by an antiestrogen. Studies using mutants of ER-α demonstrated that Akt increased estrogen receptor activity through the amino-terminal activation function-1 (AF-1). Serines S104 S106, S118, and S167 appear to play a role in the activation of ER-α by Akt.

Original languageEnglish (US)
Pages (from-to)4503-4511
Number of pages9
JournalEndocrinology
Volume141
Issue number12
DOIs
StatePublished - Jan 1 2000

ASJC Scopus subject areas

  • Endocrinology

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    Martin, M. B., Franke, T. F., Stoica, G. E., Chambon, P., Katzenellenbogen, B. S., Stoica, B. A., McLemore, M. S., Olivo, S. E., & Stoica, A. (2000). A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. Endocrinology, 141(12), 4503-4511. https://doi.org/10.1210/endo.141.12.7836