Transient versus sustained phosphorylation and nuclear accumulation of ERKs underlie anti-versus pro-apoptotic effects of estrogens.
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.
Chen
Jin-Ran
JR
Division of Endocrinology & Metabolism, Center for Osteoporosis & Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Health Care System, Little Rock, Arkansas 72205, USA.
Plotkin
Lilian I
LI
Aguirre
José Ignacio
JI
Han
Li
L
Jilka
Robert L
RL
Kousteni
Stavroula
S
Bellido
Teresita
T
Manolagas
Stavros C
SC
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009154:Mutation; D010010:Osteoclasts / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D004967:Estrogens; D005231:Fatty Acids, Unsaturated; D049452:Green Fluorescent Proteins; D004958:Estradiol; D005047:Etoposide; D002772:Cholera Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; C038753:leptomycin B