β-Estradiol-dependent activation of the JAK/STAT pathway requires p/CIP and CARM1.

Abstract

The steroid receptor coactivator p/CIP, also known as SRC-3, is an oncogene commonly amplified in breast and ovarian cancers. p/CIP is known to associate with coactivator arginine methyltransferase 1 (CARM1) on select estrogen responsive genes. We have shown, using a ChIP-on-chip approach, that in response to stimulation with 17β-estradiol (E2), the p/CIP/CARM1 complex is recruited to 204 proximal promoters in MCF-7 cells. Many of the complex target genes have been previously implicated in signaling pathways related to oncogenesis. Jak2, a member of the Jak/Stat signaling cascade, is one of the direct E2-dependent targets of the p/CIP/CARM1 complex. Following E2-treatment, histone modifications at the Jak2 promoter are reflective of a transcriptionally permissive gene, and modest changes in RNA and protein expression lead us to suggest that an additional factor(s) may be required for a more notable transcriptional and functional response. Bioinformatic examination of the 204 proximal promoter sequences of p/CIP/CARM1 targets supports the idea that transcription factor crosstalk is likely the favored mechanism of E2-dependent p/CIP/CARM1 complex recruitment. This data may have implications towards understanding the oncogenic role of p/CIP in breast cancer and ultimately allow for the identification of new prognostic indicators and/or viable therapeutic targets.

• Authors: N Coughlan, G Thillainadesan, J Andrews, M Isovic, J Torchia
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1833 Issue 6 Pg. 1463-75 (Jun 2013) ISSN: 0006-3002 [Print] Netherlands
• PMID: 23434684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers, Tumor
• CARD Signaling Adaptor Proteins
• Chromatin
• Estrogens
• RNA, Messenger
• STAT1 Transcription Factor
• STAT1 protein, human
• Estradiol
• NCOA3 protein, human
• Nuclear Receptor Coactivator 3
• JAK1 protein, human
• Janus Kinase 1
• CARD11 protein, human
• Guanylate Cyclase

Topics

• Biomarkers, Tumor (genetics, metabolism)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• CARD Signaling Adaptor Proteins (genetics, metabolism)
• Chromatin (genetics)
• Chromatin Immunoprecipitation
• Estradiol (pharmacology)
• Estrogens (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Guanylate Cyclase (genetics, metabolism)
• Humans
• Janus Kinase 1 (genetics, metabolism)
• Nuclear Receptor Coactivator 3 (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• Promoter Regions, Genetic (genetics)
• Protein Binding
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• STAT1 Transcription Factor (genetics, metabolism)
• Signal Transduction
• Transcription, Genetic
• Tumor Cells, Cultured