Journal
JOURNAL OF MOLECULAR ENDOCRINOLOGY
Volume 40, Issue 3-4, Pages 173-184Publisher
BIOSCIENTIFICA LTD
DOI: 10.1677/JME-07-0165
Keywords
-
Categories
Funding
- Cancer Research UK Funding Source: Medline
Ask authors/readers for more resources
Phosphorylation of estrogen receptor-alpha (ER alpha) at specific residues in transcription activation function 1 (AF-1) can stimulate ER alpha activity in a ligand-independent manner. This has led to the proposal that AF-1 phosphorylation and the consequent increase in ER alpha activity could contribute to resistance to endocrine therapies in breast cancer patients. Previous studies have shown that serine 118 (S118) in AF-1 is phosphorylated by extracellular signal-regulated kinases 1 and 2 (Erk1/2) mitogen-activated protein kinase (MAPK) in a ligand-independent manner. Here, we show that serines 104 (S104) and 106 (S106) are also phosphorylated by MAPK in vitro and upon stimulation of MAPK activity in vivo. Phosphorylation of S104 and S106 can be inhibited by the MAP-erk kinase (MEK)1/2 inhibitor U0126 and by expression of kinase-dead Raf1. Further, we show that, although S118 is important for the stimulation of ER alpha activity by the selective ER modulator 4-hydroxytamoxifen (OHT), S104 and S106 are also required for the agonist activity of OHT. Acidic amino acid substitution of S104 or S106 stimulates ER alpha activity to a greater extent than the equivalent substitution at S118, suggesting that phosphorylation at S104 and S106 is important for ER alpha activity. Collectively, these data indicate that the MAPK stimulation of ER alpha activity involves the phosphorylation not only of S118 but also of S104 and S106, and that MAPK-mediated hyperphosphorylation of ER alpha at these sites may contribute to resistance to tamoxifen in breast cancer.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available