Estrogen receptor (ER)alpha-mediated non genomic events are now defined as necessary and sufficient for 17-estradiol (E2)-induced cell cycle-regulating genes (e.g., cyclin D1) and G1/S phase transition. Although ER interaction with specific membrane proteins and ER lipid modifications have been proposed for ER membrane localization, the biochemical bases for ER interaction with the plasma membrane are unknown. As a potential mechanism, we demonstrated that S-palmitoylation of the Cys447 residue may explain the ability of ER to associate to plasma membrane making possible E2-dependent rapid functions. Cell lines expressing transfected or endogenous human ER (HeLa and HepG2, respectively) or the ER non-palmitoylable Cys447Ala mutant transfected in HeLa cells have been used as experimental models. Here, we report direct evidence that ER is a palmitoylated protein. The mutation of the Cys447 residue to Ala impairs ER palmitoylation and results in the loss of ER plasma membrane localization and interaction with caveolin-1. In turn, E2-induced rapid non-genomic signals (i.e., ERK and AKT activation, cyclin D1 promoter activity and DNA synthesis) are also prevented. Remarkably, both ER palmitoylation and its interaction with caveolin-1 are slowly reduced by E2 in time and dose dependent fashion. The cell stimulation with other ER ligands (i.e., naringenin, a natural flavonoid broadly present in the western diet, and tamoxifen) induces an extremely rapid reduction of ER palmitoylation and its interaction with caveolin-1, impairing the activation of signal molecules (AKT and ERK-2 phoshorylation). As a whole, these data indicate that palmitoylation can be regarded as a regulatory device enabling ERalpha to initiate non-genomic signal transduction pathways that lead cell to proliferate.
Galluzzo, P., Marino, M. (2005). LIGAND-INDUCED REGULATION OF ER alpha PALMITOYLATION. In European Network of Excellence CASCADE Summer School on Endocrinology: Nuclear Receptors and their Ligands in Metabolism and Disease Bregenz, Austria. (pp.15). non disponibile : non disponibile.
LIGAND-INDUCED REGULATION OF ER alpha PALMITOYLATION
GALLUZZO, PAOLA;MARINO, Maria
2005-01-01
Abstract
Estrogen receptor (ER)alpha-mediated non genomic events are now defined as necessary and sufficient for 17-estradiol (E2)-induced cell cycle-regulating genes (e.g., cyclin D1) and G1/S phase transition. Although ER interaction with specific membrane proteins and ER lipid modifications have been proposed for ER membrane localization, the biochemical bases for ER interaction with the plasma membrane are unknown. As a potential mechanism, we demonstrated that S-palmitoylation of the Cys447 residue may explain the ability of ER to associate to plasma membrane making possible E2-dependent rapid functions. Cell lines expressing transfected or endogenous human ER (HeLa and HepG2, respectively) or the ER non-palmitoylable Cys447Ala mutant transfected in HeLa cells have been used as experimental models. Here, we report direct evidence that ER is a palmitoylated protein. The mutation of the Cys447 residue to Ala impairs ER palmitoylation and results in the loss of ER plasma membrane localization and interaction with caveolin-1. In turn, E2-induced rapid non-genomic signals (i.e., ERK and AKT activation, cyclin D1 promoter activity and DNA synthesis) are also prevented. Remarkably, both ER palmitoylation and its interaction with caveolin-1 are slowly reduced by E2 in time and dose dependent fashion. The cell stimulation with other ER ligands (i.e., naringenin, a natural flavonoid broadly present in the western diet, and tamoxifen) induces an extremely rapid reduction of ER palmitoylation and its interaction with caveolin-1, impairing the activation of signal molecules (AKT and ERK-2 phoshorylation). As a whole, these data indicate that palmitoylation can be regarded as a regulatory device enabling ERalpha to initiate non-genomic signal transduction pathways that lead cell to proliferate.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
