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

Endocrinology. 2000 Dec;141(12):4503-11. doi: 10.1210/endo.141.12.7836.

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-alpha. 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-alpha 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-alpha 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-alpha and the dominant negative Akt mutant in COS-1 cells also blocked the growth factor-stimulated activation of ER-alpha, but coexpression of the wild-type receptor with the constitutively active Akt mutant increased ER-alpha activity. Receptor activation was blocked by an antiestrogen. Studies using mutants of ER-alpha 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-alpha by Akt.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • COS Cells
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Epidermal Growth Factor / physiology*
  • Estrogen Receptor alpha
  • Estrogens / physiology*
  • Gene Expression
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / physiology*
  • Mutation
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / analysis
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / physiology*
  • Receptors, Progesterone / genetics
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • Estrogen Receptor alpha
  • Estrogens
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Epidermal Growth Factor
  • Insulin-Like Growth Factor I
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt