Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus. Physiol Genomics 29: 13-23, 2007; doi:10.1152 doi:10. /physiolgenomics.00291.2005 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.17␤-estradiol; 17␤-estradiol modulation; ovariectomized mice; oligonucleotide microarray; protein tyrosine phosphatase IN MAMMALS, THE UTERUS of a mature female undergoes multiple changes during the estrous cycle that reflect modifications of the uterine endometrium in continuous preparation for embryo implantation. Since the majority of cycles are not associated with conception, they often lead to endometrial degeneration and menstrual bleeding. The endometrium thus exhibits a cyclic pattern of growth, regression, disruption, bleeding, and regeneration throughout reproductive life. These changes are mainly under the control of estrogens, progesterone, and androgens. Disregulation of the uterine vasculature has been found to accompany different sex steroid disturbances (28).17␤-Estradiol (E2) is well known to play the key role in mammalian endometrial physiology, since the proliferation of endometrial cells and the extension of spiral vessels that occur during the proliferative phase of the menstrual cycle are controlled by E2 (20, 46). Estrogen is also frequently associated with endometrial cancer, which comprises two subtypes: endometrioid carcinomas (type I) related to estrogen exposure and nonendometrioid carcinomas (type II), which are independent of E2 action (16). Type I cancers ar...

In rodents, the uterus of a mature female undergoes changes during the uterine cycle, under the control of steroid hormones. 5alpha-Dihydrotestosterone (DHT) is recognized to play an important role in the regulation of androgen action in normal endometrium. Using microarray technology, a screening analysis of genes responding to DHT in the uterus of ovariectomized mice, has allowed us to highlight multiple genes of the ATM/Gadd45g pathway that are modulated following exposure to DHT. Two phases of regulation were identified. In the early phase, the expression of genes involved in the G2/M arrest is rapidly increased, followed by the repression of genes of the G1/S checkpoint, and by the induction of transcriptional regulators. Later, i.e. from 12 to 24 hr, genes involved in G2/M transition, cytoarchitectural and lipid-related genes are stimulated by DHT while immunity-related genes appear to be differentially regulated by the hormone. These results show that a physiological dose of DHT induces the transcription of genes promoting the cell cycle progression in mice. Profile determination of temporal uterine gene expression at the transcriptional level enables us to suggest that the DHT modulation of genes involved in ATM/Gadd45g signaling in an ATM- or p53-independent manner, could play an important role in the cyclical changes of uterine cells in the mouse uterus.