Estrogen regulation of c-fos gene expression through phosphatidylinositol-3-kinase-dependent activation of serum response factor in MCF-7 breast cancer cells.
17Beta-estradiol (E2) induces proliferation and c-fos gene expression in MCF-7 cells and both responses are partially blocked by wortmannin and LY294002 which are inhibitors of phosphatidylinositol-3-kinase (PI3-K). Analysis of the c-fos gene promoter shows that the effects of wortmannin and LY294002 are associated with inhibition of E2-induced activation through the serum response factor (SRF) motif within the proximal serum response element at -325 and -296. E2 activates constructs containing multiple copies of the SRF (pSRF) and a GAL4-SRF fusion protein; these responses are accompanied by PI3-K-dependent phosphorylation of Akt and inhibited by wortmannin/LY294002, the antiestrogen ICI 182780, but not by the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD98059. Using a series of kinase inhibitors and dominant negative kinase expression plasmids, it was shown that the non-genomic activation of SRF by E2 was associated with src-ras-PI3-K pathway, thus, demonstrating hormonal activation of the SRE through src-ras activation of both PI3-K- and MAPK-dependent signaling pathways.
Duan
Renqin
R
Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA.
Xie
Wen
W
Li
Xiangrong
X
McDougal
Andrew
A
Safe
Stephen
S
D000730:Androstadienes / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D000077191:Wortmannin; D050807:ets-Domain Protein Elk-1
D000730:Androstadienes; D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D004958:Estradiol; D006133:Growth Substances; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D026362:Serum Response Factor; D014157:Transcription Factors; D000077191:Wortmannin; D050807:ets-Domain Protein Elk-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one