Synergistic action of prolactin (PRL) and androgen on PRL-inducible protein gene expression in human breast cancer cells: a unique model for functional cooperation between signal transducer and activator of transcription-5 and androgen receptor
| Autor: | Sebastien Gingras, Jean-Louis Carsol, Jacques Simard |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Transcriptional Activation
medicine.drug_class 5' Flanking Region Molecular Sequence Data STAT5B Breast Neoplasms Biology Response Elements Endocrinology Prolactin-induced protein medicine STAT5 Transcription Factor Tumor Cells Cultured Animals Humans Promoter Regions Genetic Molecular Biology Apolipoproteins D Conserved Sequence Glycoproteins Reporter gene Binding Sites Base Sequence RNF4 Tumor Suppressor Proteins food and beverages Membrane Transport Proteins Dihydrotestosterone Drug Synergism General Medicine Androgen Milk Proteins Molecular biology Prolactin Androgen receptor DNA-Binding Proteins Gene Expression Regulation Neoplastic Apolipoproteins Nuclear receptor Receptors Androgen Mutation Trans-Activators Female Carrier Proteins medicine.drug Signal Transduction |
| Zdroj: | Molecular endocrinology (Baltimore, Md.). 16(7) |
| ISSN: | 0888-8809 |
| Popis: | The signal transducer and activator of transcription 5 (Stat5) has been shown to cooperate with some nuclear receptors. However, an interaction has never been demonstrated with the androgen receptor (AR). Given that the PRL-inducible protein/gross cystic disease fluid-15 (PIP/GCDFP-15) is both a PRL-controlled and an androgen-controlled protein, we used its promoter region to investigate the potential interaction between Stat5 and androgen receptor. Dihydrotestosterone or PRL alone slightly modulated or did not modulate the luciferase activity of all reporter gene constructs. In contrast, a maximal increase was observed using the −1477+42 reporter gene construct after exposure to both dihydrotestosterone and PRL. The requirement of half-site androgen-responsive elements and two consensus Stat5-binding elements, Stat5#1 and Stat5#2, was determined by site-directed mutagenesis. Activated Stat5B binds with a higher affinity to Stat5#2 than to Stat5#1. Stat5AΔ749 and Stat5BΔ754 mutants demonstrated that the Stat5 trans-activation domain is involved in the hormonal cooperation. The cooperation depends on the PRL-induced phosphorylation on Tyr694 in Stat5A and Tyr699 in Stat5B, as demonstrated using the Stat5AY694F and Stat5BY699F proteins. The use of AR Q798E, C619Y, and C784Y mutants showed that trans-activation, DNA-binding, and ligand-binding domains of AR are essential. Our study thus suggests a functional cooperation between AR and Stat5. |
| Databáze: | OpenAIRE |
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