Table of Contents
Journal of Signal Transduction
Volume 2012 (2012), Article ID 204236, 12 pages
http://dx.doi.org/10.1155/2012/204236
Research Article

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

1Molecular 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
2Cellular and Molecular Pathology Branch, 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
3Biostatistics Branch, 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

Received 2 March 2012; Accepted 22 July 2012

Academic Editor: Bertrand Jean-Claude

Copyright © 2012 Linda Yu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 (ER ) signaling. We determined the genomic and nongenomic effects of 17 -estradiol (E2) on IGF-IR/MAPKp44/42 signaling and gene expression in human UtLM cells with intact or silenced IGF-IR. Analysis by RT2 Profiler PCR-array showed genes involved in IGF-IR/MAPK signaling were upregulated in UtLM cells by E2 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. E2 rapidly activated IGF-IR/MAPKp44/42 signaling nongenomically and induced phosphorylation of ER at ser118 in cells with a functional IGF-IR versus those without. E2 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.