Transient versus sustained phosphorylation and nuclear accumulation of ERKs underlie anti- versus pro-apoptotic effects of estrogens

Jin Ran Chen, Lilian I. Plotkin, José Ignacio Aguirre, Li Han, Robert L. Jilka, Stavroula Kousteni, Teresita Bellido, Stavros C. Manolagas

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121 Scopus citations


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 17β-estradiol 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.

Original languageEnglish (US)
Pages (from-to)4632-4638
Number of pages7
JournalJournal of Biological Chemistry
Issue number6
StatePublished - Feb 11 2005


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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