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

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

Research output: Contribution to journalArticle

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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 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
Volume280
Issue number6
DOIs
StatePublished - Feb 11 2005
Externally publishedYes

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Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Estrogens
Estradiol
Osteoclasts
Osteocytes
Chemical activation
Kinetics
Cholera Toxin
Osteoblasts
Cyclic AMP-Dependent Protein Kinases
Green Fluorescent Proteins
Adenylyl Cyclases
Bone
Steroids
Hormones
Tissue
Bone and Bones

ASJC Scopus subject areas

  • Biochemistry

Cite this

Transient versus sustained phosphorylation and nuclear accumulation of ERKs underlie anti- versus pro-apoptotic effects of estrogens. / Chen, Jin Ran; Plotkin, Lilian; Aguirre, José Ignacio; Han, Li; Jilka, Robert L.; Kousteni, Stavroula; Bellido, Teresita; Manolagas, Stavros C.

In: Journal of Biological Chemistry, Vol. 280, No. 6, 11.02.2005, p. 4632-4638.

Research output: Contribution to journalArticle

Chen, Jin Ran ; Plotkin, Lilian ; Aguirre, José Ignacio ; Han, Li ; Jilka, Robert L. ; Kousteni, Stavroula ; Bellido, Teresita ; Manolagas, Stavros C. / Transient versus sustained phosphorylation and nuclear accumulation of ERKs underlie anti- versus pro-apoptotic effects of estrogens. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 6. pp. 4632-4638.
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