当前位置： SCI文献检索 > ONCOGENE期刊下所有文献 > Heregulin-beta1 regulates the estrogen receptor-alpha gene expression and activity via the ErbB2/PI 3-K/Akt pathway.

Heregulin-beta1 regulates the estrogen receptor-alpha gene expression and activity via the ErbB2/PI 3-K/Akt pathway.

Abstract：

:This study examines whether the serine/threonine protein kinase, Akt, is involved in the crosstalk between the ErbB2 and estrogen receptor-alpha (ER-alpha) pathways. Treatment of MCF-7 cells with 10(-9) M heregulin-beta1 (HRG-beta1) resulted in a rapid phosphorylation of Akt and a 15-fold increase in Akt activity. Akt phosphorylation was blocked by inhibitors of phosphatidylinositol 3-kinase (PI 3-K), by antiestrogens, the protein tyrosine kinase inhibitor, genistein, and by AG825, a selective ErbB2 inhibitor; but not by AG30, a selective EGFR inhibitor. Akt phosphorylation by HRG-beta1 was abrogated by an arginine to cysteine mutation (R25C) in the pleckstrin homology (PH) domain of Akt, and HRG-beta1 did not induce Akt phosphorylation in the ER-negative variant of MCF-7, MCF-7/ADR. Transient transfection of ER-alpha into these cells restored Akt phosphorylation by HRG-beta1, suggesting the requirement of ER-alpha. HRG-beta1 did not activate Akt in MCF-7 cells stably transfected with an anti-ErbB2-targeted ribozyme, further confirming a role for ErbB2. Stable transfection of the cells with a dominant negative Akt or with the R25C-Akt mutant, as well as PI 3-K inhibitors, blocked the effect of HRG-beta1 on ER-alpha expression and activity and on the growth of MCF-7 cells. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of HRG-beta1. Experiments employing selective ErbB inhibitors demonstrate that the effect of HRG-beta1 on ER-alpha expression and activity is also mediated by ErbB2 and not by EGFR, demonstrating that ErbB2 is the primary mediator of the effects of HRG-beta1 on ER-alpha regulation. Taken together, our data suggest that HRG-beta1, bound to the ErbB2 ErbB3 heterodimer, in the presence of membrane ER-alpha, interacts with and activates PI 3-K/Akt. Akt leads to nuclear ER-alpha phosphorylation, thereby altering its expression and transcriptional activity.

journal_name

Oncogene

journal_title

Oncogene

authors

Stoica GE,Franke TF,Wellstein A,Morgan E,Czubayko F,List HJ,Reiter R,Martin MB,Stoica A

doi

10.1038/sj.onc.1206311

subject

Has Abstract

pub_date

2003-04-10 00:00:00

pages

2073-87

issue

eissn

0950-9232

issn

1476-5594

pii

1206311

journal_volume

pub_type

杂志文章,收录出版

在线工具

Heregulin-beta1 regulates the estrogen receptor-alpha gene expression and activity via the ErbB2/PI 3-K/Akt pathway.