title: Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells.
abstract: Estrogen and growth factors play a major role in uterine leiomyoma (UtLM) growth possibly through interactions of receptor tyrosine kinases (RTKs) and estrogen receptor-alpha (ERα) signaling. We determined the genomic and nongenomic effects of 17β-estradiol (E(2)) on IGF-IR/MAPKp44/42 signaling and gene expression in human UtLM cells with intact or silenced IGF-IR. Analysis by RT(2) Profiler PCR-array showed genes involved in IGF-IR/MAPK signaling were upregulated in UtLM cells by E(2) including cyclin D kinases, MAPKs, and MAPK kinases; RTK signaling mediator, GRB2; transcriptional factors ELK1 and E2F1; CCNB2 involved in cell cycle progression, proliferation, and survival; and COL1A1 associated with collagen synthesis. Silencing (si)IGF-IR attenuated the above effects and resulted in upregulation of different genes, such as transcriptional factor ETS2; the tyrosine kinase receptor, EGFR; and DLK1 involved in fibrosis. E(2) rapidly activated IGF-IR/MAPKp44/42 signaling nongenomically and induced phosphorylation of ERα at ser118 in cells with a functional IGF-IR versus those without. E(2) also upregulated IGF-I gene and protein expression through a prolonged genomic event. These results suggest a pivotal role of IGF-IR and possibly other RTKs in mediating genomic and nongenomic hormone receptor interactions and signaling in fibroids and provide novel genes and targets for future intervention and prevention strategies.
authors.affiliation: Molecular Pathogenesis Group, National Toxicology Program (NTP) Laboratory, NTP, Department of Health and Human Services (DHHS), National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, NC 27709, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Yu
authors.forename: Alicia B
authors.initials: AB
authors.lastname: Moore
authors.forename: Lysandra
authors.initials: L
authors.lastname: Castro
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Gao
authors.forename: Hoang-Long C
authors.initials: HL
authors.lastname: Huynh
authors.forename: Michelle
authors.initials: M
authors.lastname: Klippel
authors.forename: Norris D
authors.initials: ND
authors.lastname: Flagler
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kissling
authors.forename: Darlene
authors.initials: D
authors.lastname: Dixon