文档介绍：0888-8809/07/$ Molecular Endocrinology 21(2):439–456
Printed in . Copyright © 2007 by The Endocrine Society
doi: -0059
Protein Kinase A Exhibits Selective Modulation of
Estradiol-Dependent Transcription in Breast Cancer
Cells that Is Associated with Decreased Ligand
Binding, Altered Estrogen Receptor ␣ Promoter
Interaction, and Changes in Receptor
Phosphorylation
Mariam H. Al-Dhaheri and Brian G. Rowan
Department of Biochemistry and Cancer Biology, Health Science Campus, University of Toledo,
Toledo, Ohio 43614
Inhibition of protein kinase A (PKA) promotes es- cyclin D1 mRNA and protein in MCF7 cells. To
trogen-dependent growth of MCF7 breast cancer explore likely mechanisms by which F/I regulated
cells, although the mechanisms by which PKA reg- ER, experiments examined estradiol binding,
ulates estrogen receptor (ER) function remain un- Hsp90 interaction, promoter recruitment, and ER␣
clear. In this study elevation of cAMP by forskolin/ phosphorylation. F/I decreased estradiol binding
3-isobutyl-1-methylxanthine (F/I) suppressed and increased Hsp90 association with ER␣. Chro-
estradiol-dependent MCF7 and T47D breast can- matin immunoprecipitation revealed that F/I re-
cer cell growth but not tamoxifen-resistant MCF7- cruited ER␣ to both pS2 and cMyc promoters at
LCC2 cells. Although F/I induced ligand indepen- earlier times than estradiol, and F/I shifted estra-
dent activation of ER␣, F/I also decreased diol recruitment of ER␣ to earlier time points. F/I
estradiol-dependent reporter gene transcription. induced a unique ER␣ phosphorylation profile (in-
Overexpression of PKA or PKA inhibitor (PKI) dem- crease in serine 305 and decrease in serine 118
onstrated that F/I effects on repression of estradiol phosphorylation) that was distinct from estradiol
action occurred through the PKA pathway. 8CPT- and estradiol ؉ F/I. Taken together, F/I signaling
2Me-cAMP, a selective inducer of non-PKA signal- through PKA selec