Non-transcriptional action of oestradiol and progestin triggers DNA synthesis.
The recent findings that oestradiol and progestins activate the Src/Ras/Erks signalling pathway raise the question of the role of this stimulation. Microinjection experiments of human mammary cancer-derived cells (MCF-7 and T47D) with cDNA of catalytically inactive Src or anti-Ras antibody prove that Src and Ras are required for oestradiol and progestin-dependent progression of cells through the cell cycle. The antitumoral ansamycin antibiotic, geldanamycin, disrupts the steroid-induced Ras-Raf-1 association and prevents Raf-1 activation and steroid-induced DNA synthesis. Furthermore, the selective MEK 1 inhibitor, PD 98059, inhibits oestradiol and progestin stimulation of Erk-2 and the steroid-dependent S-phase entry. The MDA-MB231 cells, which do not express oestradiol receptor, fail to respond to oestradiol in terms of Erk-2 activation and S-phase entry. Fibroblasts are made equally oestradiol-responsive in terms of DNA synthesis by transient transfection with either the wild-type or the transcriptionally inactive mutant oestradiol receptor (HE241G). Co-transfection of catalytically inactive Src as well as treatment with PD98059 inhibit the oestradiol-dependent S-phase entry of fibroblasts expressing either the wild-type oestrogen receptor or its transcriptionally inactive mutant. The data presented support the view that non-transcriptional action of the two steroids plays a major role in cell cycle progression.
Castoria
G
G
Istituto di Patologia Generale e Oncologia, Facoltà di Medicina e Chirurgia, II Università di Napoli, Largo S.Aniello a Caponapoli, 2, 80138 Napoli, Italy.
Barone
M V
MV
Di Domenico
M
M
Bilancio
A
A
Ametrano
D
D
Migliaccio
A
A
Auricchio
F
F
D016475:3T3 Cells; D000818:Animals; D016227:Benzoquinones; D001943:Breast Neoplasms / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D011905:Genes, ras; D016391:Genes, src; D006801:Humans; D047029:Lactams, Macrocyclic; D048369:MAP Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D011372:Progestins / Q000494:pharmacology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D011959:Receptors, Estradiol / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D014158:Transcription, Genetic; D018631:ras Proteins / Q000378:metabolism
D016227:Benzoquinones; D004273:DNA, Neoplasm; D005419:Flavonoids; D047029:Lactams, Macrocyclic; D011372:Progestins; D011809:Quinones; D011959:Receptors, Estradiol; D004958:Estradiol; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C001277:geldanamycin