scholarly journals Protein Kinase A Exhibits Selective Modulation of Estradiol-Dependent Transcription in Breast Cancer Cells that Is Associated with Decreased Ligand Binding, Altered Estrogen Receptor α Promoter Interaction, and Changes in Receptor Phosphorylation

2007 ◽  
Vol 21 (2) ◽  
pp. 439-456 ◽  
Author(s):  
Mariam H. Al-Dhaheri ◽  
Brian G. Rowan
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Kinase ◽  
Ligand Binding ◽  
Protein Kinase A ◽  
Breast Cancer Cells ◽  
Estrogen Receptor Α ◽  
Selective Modulation ◽  
Kinase A ◽  
Promoter Interaction

scholarly journals Phosphorylation of Human Estrogen Receptor α by Protein Kinase A Regulates Dimerization

1999 ◽  
Vol 19 (2) ◽  
pp. 1002-1015 ◽  
Author(s):  
Dongsheng Chen ◽  
Paul E. Pace ◽  
R. Charles Coombes ◽  
Simak Ali
Keyword(s):  
Estrogen Receptor ◽  
Protein Kinase ◽  
Dna Binding ◽  
Ligand Binding ◽  
Protein Kinase A ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Ici 182,780 ◽  
Kinase A

ABSTRACT Phosphorylation provides an important mechanism by which transcription factor activity is regulated. Estrogen receptor α (ERα) is phosphorylated on multiple sites, and stimulation of a number of growth factor receptors and/or protein kinases leads to ligand-independent and/or synergistic increase in transcriptional activation by ERα in the presence of estrogen. Here we show that ERα is phosphorylated by protein kinase A (PKA) on serine-236 within the DNA binding domain. Mutation of serine-236 to glutamic acid prevents DNA binding by inhibiting dimerization by ERα, whereas mutation to alanine has little effect on DNA binding or dimerization. Furthermore, PKA overexpression or activation of endogenous PKA inhibits dimerization in the absence of ligand. This inhibition is overcome by the addition of 17β-estradiol or the partial agonist 4-hydroxy tamoxifen. Interestingly, treatment with the complete antagonist ICI 182,780 does not overcome the inhibitory effect of PKA activation. Our results indicate that in the absence of ligand ERα forms dimers through interaction between DNA binding domains and that dimerization mediated by the ligand binding domain only occurs upon ligand binding but that the complete antagonist ICI 182,780 prevents dimerization through the ligand-binding domain. Heterodimer formation between ERα and ERβ is similarly affected by PKA phosphorylation of serine 236 of ERα. However, 4-hydroxytamoxifen is unable to overcome inhibition of dimerization by PKA. Thus, phosphorylation of ERα in the DNA binding domain provides a mechanism by which dimerization and thereby DNA binding by the estrogen receptor is regulated.

scholarly journals Various Phosphorylation Pathways, Depending on Agonist and Antagonist Binding to Endogenous Estrogen Receptor α (ERα), Differentially Affect ERα Extractability, Proteasome-Mediated Stability, and Transcriptional Activity in Human Breast Cancer Cells

2003 ◽  
Vol 17 (10) ◽  
pp. 2013-2027 ◽  
Author(s):  
Véronique Marsaud ◽  
Angélique Gougelet ◽  
Sébastien Maillard ◽  
Jack-Michel Renoir
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Kinase ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Kinase Inhibitors ◽  
Estrogen Receptor Α ◽  
Human Breast ◽  
Ligand Free ◽  
Mcf 7

Abstract Estrogen receptor-α (ER) is down-regulated in the presence of its cognate ligand, estradiol (E2), as well as in the presence of antiestrogens, through the ubiquitin proteasome pathway. Here, we show that, at pharmacological concentrations, the degradation rate of pure antagonist/endogenous ER complexes from human breast cancer MCF-7 cells is 10 times faster than that of ER-E2 complexes, while 4-hydroxy-tamoxifen (4-OH-T)-ER complexes are stable. Whereas pure antagonist-ER complexes are firmly bound to a nuclear compartment from which they are not extractable, the 4-OH-T-ER accumulates in a soluble cell compartment. No difference was observed in the fate of ER whether bound to pure antiestrogens ICI 182,780 or RU 58668. Cycloheximide experiments showed that, while the proteasome-mediated destruction of E2-ER (unlike that of RU 58668- and ICI 182,780-ER) complexes could implicate (or not) a protein synthesis-dependent process, both MAPKs (p38 and ERKs p44 and p42) are activated. By using a panel of kinase inhibitors/activators to study the impact of phosphorylation pathways on ER degradation, we found that protein kinase C is an enhancer of proteasome-mediated degradation of both ligand-free and ER bound to either E2, 4-OH-T, and pure antagonists. On the contrary, protein kinase A, MAPKs, and phosphatidyl-inositol-3 kinase all impede proteasome-mediated destruction of ligand free and E2-bound ER while only MAPKs inhibit the degradation of pure antiestrogens/ER species. In addition, no correlation was found between the capacity of kinase inhibitors to affect ER stability and the basal or E2-induced transcription. These results suggest that, in MCF-7 breast cancer cells, ER turnover, localization, and activity are maintained by an equilibrium between various phosphorylation pathways, which are differently modulated by ER ligands and protein kinases.

Leptin potentiates antiproliferative action of cAMP elevation via protein kinase A down-regulation in breast cancer cells

2010 ◽  
Vol 225 (3) ◽  
pp. 801-809 ◽  
Author(s):  
Silvio Naviglio ◽  
Davide Di Gesto ◽  
Fausto Illiano ◽  
Emilio Chiosi ◽  
Antonio Giordano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Down Regulation ◽  
Antiproliferative Action ◽  
Camp Elevation ◽  
Kinase A
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