Caveolin-1 potentiates estrogen receptor alpha (ERalpha) signaling. caveolin-1 drives ligand-independent nuclear translocation and activation of ERalpha.
Estrogen receptor alpha (ERalpha) is a soluble protein that mediates the effects of the gonadal estrogens such as 17beta-estradiol. Upon ligand binding, a cytoplasmic pool of ERalpha translocates to the nucleus, where it acts as a transcription factor, driving the expression of genes that contain estrogen-response elements. The activity of ERalpha is regulated by a number of proteins, including cytosolic chaperones and nuclear cofactors. Here, we show that caveolin-1 potentiates ERalpha-mediated signal transduction. Coexpression of caveolin-1 and ERalpha resulted in ligand-independent translocation of ERalpha to the nucleus as shown by both cell fractionation and immunofluorescence microscopic studies. Similarly, caveolin-1 augmented both ligand-independent and ligand-dependent ERalpha signaling as measured using a estrogen-response element-based luciferase reporter assay. Caveolin-1-mediated activation of ERalpha was sensitive to a well known ER antagonist, 4-hydroxytamoxifen. However, much higher concentrations of tamoxifen were required to mediate inhibition in the presence of caveolin-1. Interestingly, caveolin-1 expression also synergized with a constitutively active, ligand-independent ERalpha mutant, dramatically illustrating the potent stimulatory effect of caveolin-1 in this receptor system. Taken together, our results identify caveolin-1 as a new positive regulator of ERalpha signal transduction.
Schlegel
A
A
Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Wang
C
C
Katzenellenbogen
B S
BS
Pestell
R G
RG
Lisanti
M P
MP
D001692:Biological Transport; D051242:Caveolin 1; D022461:Caveolins; D002467:Cell Nucleus / Q000378:metabolism*; D047628:Estrogen Receptor alpha; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D047628:Estrogen Receptor alpha; D008024:Ligands; D008565:Membrane Proteins; D011960:Receptors, Estrogen