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

J Biol Chem. 2005 Feb 11;280(6):4632-8. doi: 10.1074/jbc.M411530200. Epub 2004 Nov 22.


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 17beta-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), 17beta-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 17beta-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 17beta-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Apoptosis*
  • Blotting, Western
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Cholera Toxin / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cytoplasm / metabolism
  • Enzyme Activation
  • Estradiol / metabolism
  • Estrogens / metabolism*
  • Etoposide / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Fatty Acids, Unsaturated / pharmacology
  • Green Fluorescent Proteins / metabolism
  • Kinetics
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mutation
  • Osteoclasts / metabolism
  • Phosphorylation
  • Plasmids / metabolism
  • Time Factors
  • Transfection


  • Estrogens
  • Fatty Acids, Unsaturated
  • Green Fluorescent Proteins
  • Estradiol
  • Etoposide
  • Cholera Toxin
  • Cyclic AMP-Dependent Protein Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 1
  • leptomycin B