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Transient Versus Sustained Phosphorylation and Nuclear Accumulation of ERKs Underlie Anti Versus Pro-apoptotic Effects of Estrogens.

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Title: Transient Versus Sustained Phosphorylation and Nuclear Accumulation of ERKs Underlie Anti Versus Pro-apoptotic Effects of Estrogens.
Authors: Jin-Ran Chen1, Plotkin, Lilian I.1, Aguirre, José Ignacio1, Li Han1, Jilka, Robert L.1, Kousteni, Stavroula1, Bellido, Teresita1, Manolagas, Stavros C.1 manolagasstavros@uams.edu
Source: Journal of Biological Chemistry. 2/11/2005, Vol. 280 Issue 6, p4632-4638. 7p. 3 Color Photographs, 9 Graphs.
Subjects: Steroids, Osteocytes, Apoptosis, Phosphorylation, Estradiol, Osteoclasts
Abstract: Sex steroids exert anti-apoptotic effects on osteoblasts/osteocytes but exert pro-apoptotic effects on osteoclasts, in both cases requiring activation of the extracellular signal-regulated kinases (ERKs). To explain the mechanistic basis of this divergence, we searched for differences in the kinetics of phosphorylation and/or in the subcellular localization of ERKs in response to 17βestradiol in the two cell types. In contrast to its transient effect on ERK phosphorylation in osteocytic cells (return to base line by 30 min), 17β-estradiol-induced ERK phosphorylation in osteoclasts was sustained for at least 24 h following exposure to the hormone. Conversion of sustained ERK phosphorylation to transient, by means of cholera toxin-induced activation of the adenylate cyclase/cAMP/protein kinase A pathway, abrogated the pro-apoptotic effect of 17β-estradiol on osteoclasts. Conversely, prolongation of ERK activation in osteocytes, by means of leptomycin B-induced inhibition of ERK export from the nucleus or overexpression of a green fluorescent protein-ERK2 mutant that resides permanently in the nucleus, converted the anti-apoptotic effect of 17β-estradiol to a pro-apoptotic one. These findings indicate that the kinetics of ERK phosphorylation and the length of time that phospho-ERKs are retained in the nucleus are responsible for pro- versus anti-apoptotic effects of estrogen on different cell types of bone and perhaps their many other target tissues. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
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Abstract:Sex steroids exert anti-apoptotic effects on osteoblasts/osteocytes but exert pro-apoptotic effects on osteoclasts, in both cases requiring activation of the extracellular signal-regulated kinases (ERKs). To explain the mechanistic basis of this divergence, we searched for differences in the kinetics of phosphorylation and/or in the subcellular localization of ERKs in response to 17βestradiol in the two cell types. In contrast to its transient effect on ERK phosphorylation in osteocytic cells (return to base line by 30 min), 17β-estradiol-induced ERK phosphorylation in osteoclasts was sustained for at least 24 h following exposure to the hormone. Conversion of sustained ERK phosphorylation to transient, by means of cholera toxin-induced activation of the adenylate cyclase/cAMP/protein kinase A pathway, abrogated the pro-apoptotic effect of 17β-estradiol on osteoclasts. Conversely, prolongation of ERK activation in osteocytes, by means of leptomycin B-induced inhibition of ERK export from the nucleus or overexpression of a green fluorescent protein-ERK2 mutant that resides permanently in the nucleus, converted the anti-apoptotic effect of 17β-estradiol to a pro-apoptotic one. These findings indicate that the kinetics of ERK phosphorylation and the length of time that phospho-ERKs are retained in the nucleus are responsible for pro- versus anti-apoptotic effects of estrogen on different cell types of bone and perhaps their many other target tissues. [ABSTRACT FROM AUTHOR]
ISSN:00219258
DOI:10.1074/jbc.M411530200