Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus.
17beta-Estradiol (E2) is well known to be associated with uterine cancer, endometriosis, and leiomyomas. Although insulin-like growth factor I (IGF-I) has been identified as a mediator of the uterotrophic effect of E2 in several studies, this mechanism is still not well understood. In the present study, identification of the genes modulated by a physiological dose of E2, in the uterus, has been done in ovariectomized mice using Affymetrix microarrays. The E2-induced genomic profile shows that multiple genes belonging to the IGF-I pathway are affected after exposure to E2. Two phases of regulation could be identified. First, from 0 to 6 h, the expression of genes involved in the cell cycle, growth factors, protein tyrosine phosphatases, and MAPK phosphatases is quickly upregulated by E2, while IGF-I receptor and several genes of the MAPK and phosphatidylinositol 3-kinase pathways are downregulated. Later, i.e., from 6 to 24 h, transporters and peptidases/proteases are stimulated, whereas defense-related genes are differentially regulated by E2. Finally, cytoarchitectural genes are modulated later. The present data show that a physiological dose of E2 induces, within 24 h, a series of transcriptional events that promote the uterotrophic effect. Among these, the E2-mediated activation of the IGF-I pathway seems to play a pivotal role in the uterotrophic effect. Furthermore, the protein tyrosine phosphatases and MAPK phosphatases are likely to modulate the estrogenic uterotrophic action by targeting, at different steps, the IGF-I pathway.
Ivanga
Mahinè
M
Oncology and Molecular Endocrinology Research Center, Centre Hospitalier de l'Université Laval Research Center, Centre Hospitalier Universitaire de Québec, Department of Anatomy and Physiology, Laval University, Quebec, Canada.
Labrie
Yvan
Y
Calvo
Ezequiel
E
Belleau
Pascal
P
Martel
Céline
C
Luu-The
Van
V
Morissette
Jean
J
Labrie
Fernand
F
Durocher
Francine
F
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D017931:DNA Primers; D054638:Dual Specificity Phosphatase 1; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014599:Uterus / Q000378:metabolism* / Q000502:physiology
D018797:Cell Cycle Proteins; D017931:DNA Primers; D017874:Immediate-Early Proteins; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases