11108261

pubmed:Citation

12

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.

eng

AIM

MEDLINE

0013-7227

Print

NLM

4503-11

pubmed-meshheading:11108261-Animals, pubmed-meshheading:11108261-COS Cells, pubmed-meshheading:11108261-Enzyme Activation, pubmed-meshheading:11108261-Enzyme Inhibitors, pubmed-meshheading:11108261-Epidermal Growth Factor, pubmed-meshheading:11108261-Estrogen Receptor alpha, pubmed-meshheading:11108261-Estrogens, pubmed-meshheading:11108261-Gene Expression, pubmed-meshheading:11108261-Humans, pubmed-meshheading:11108261-Insulin-Like Growth Factor I, pubmed-meshheading:11108261-Mutation, pubmed-meshheading:11108261-Phosphatidylinositol 3-Kinases, pubmed-meshheading:11108261-Phosphorylation, pubmed-meshheading:11108261-Protein-Serine-Threonine Kinases, pubmed-meshheading:11108261-Proto-Oncogene Proteins, pubmed-meshheading:11108261-Proto-Oncogene Proteins c-akt, pubmed-meshheading:11108261-RNA, Messenger, pubmed-meshheading:11108261-Receptors, Estrogen, pubmed-meshheading:11108261-Receptors, Progesterone, pubmed-meshheading:11108261-Transfection, pubmed-meshheading:11108261-Tumor Cells, Cultured

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

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