Estrogens and ICI182,780 (Faslodex) modulate mitosis and cell death in immature cerebellar neurons via rapid activation of p44/p42 mitogen-activated protein kinase

Jeremy K. Wong, Hoa H. Le, A. Zsarnovszky, Scott M. Belcher

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Abstract

Estrogen influences the development and function of the nervous system through estrogen receptor-dependent changes in gene expression and by rapidly influencing diverse intracellular signaling pathways. We have investigated the influence of estradiol on developing neonatal rat cerebellar neurons in primary culture and found that low concentrations of 17β-estradiol (17β-E2), 17α-E2, 17β-E2-BSA, and ICI182,780 stimulated phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) mitogen-activated protein kinases (MAPK). Neither testosterone nor progesterone increased ERK1/2 phosphorylation. The effects of the estrogens were specific to the ERK1/2 MAPK pathway and were blocked by U0126, an inhibitor of the ERK1/2 MAPK kinase (MEK1/2). Compared with control cultures, significant MAPK-dependent decreases in viable granule cell numbers were observed in dissociated explant cultures of developing cerebellar neurons 24-96 hr after pulse treatment with 10 pM 17β-E2 or 10 nM ICI182,780. In contrast, continuous exposure to 10 pM 17β-E2 significantly increased granule cell numbers. Analysis of bromodeoxyuridine incorporation revealed that a 15 min pulsed treatment with 10 pM 17β-E2 increased mitogenesis, whereas continuous exposure to the same concentration of 17β-E2 was anti-mitotic. Estradiol did not increase caspase activity; however, significant increases in cellular permeability and lysis were observed. Cell lysis and death were independent of the pan-caspase inhibitor zVAD-fmk but were blocked fully by the irreversible calpain inhibitor PD150606. These results indicate that rapid activation of the ERK1/2 MAPK pathway by low concentrations of 17β-E2 induces oncotic/necrotic, but not apoptotic, programmed cell death in a subpopulation of developing granule cells and increased mitogenesis of the granule cell neuroblasts refractory to estrogen-induced neurotoxicity.

Original languageEnglish
Pages (from-to)4984-4995
Number of pages12
JournalJournal of Neuroscience
Volume23
Issue number12
Publication statusPublished - Jun 15 2003

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Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Mitosis
Estrogens
Mitogen-Activated Protein Kinases
Cell Death
Neurons
Estradiol
MAP Kinase Kinase 2
Cell Count
Phosphorylation
Caspase Inhibitors
Bromodeoxyuridine
Caspases
Estrogen Receptors
Nervous System
Progesterone
Testosterone
Permeability
fulvestrant

Keywords

  • Cerebellum
  • Development
  • ERK
  • Estradiol
  • Estrogen
  • Granule cell
  • MAPK
  • Necrosis
  • Neuron
  • Neurotoxicity
  • Oncosis

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Estrogens and ICI182,780 (Faslodex) modulate mitosis and cell death in immature cerebellar neurons via rapid activation of p44/p42 mitogen-activated protein kinase. / Wong, Jeremy K.; Le, Hoa H.; Zsarnovszky, A.; Belcher, Scott M.

In: Journal of Neuroscience, Vol. 23, No. 12, 15.06.2003, p. 4984-4995.

Research output: Contribution to journalArticle

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abstract = "Estrogen influences the development and function of the nervous system through estrogen receptor-dependent changes in gene expression and by rapidly influencing diverse intracellular signaling pathways. We have investigated the influence of estradiol on developing neonatal rat cerebellar neurons in primary culture and found that low concentrations of 17β-estradiol (17β-E2), 17α-E2, 17β-E2-BSA, and ICI182,780 stimulated phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) mitogen-activated protein kinases (MAPK). Neither testosterone nor progesterone increased ERK1/2 phosphorylation. The effects of the estrogens were specific to the ERK1/2 MAPK pathway and were blocked by U0126, an inhibitor of the ERK1/2 MAPK kinase (MEK1/2). Compared with control cultures, significant MAPK-dependent decreases in viable granule cell numbers were observed in dissociated explant cultures of developing cerebellar neurons 24-96 hr after pulse treatment with 10 pM 17β-E2 or 10 nM ICI182,780. In contrast, continuous exposure to 10 pM 17β-E2 significantly increased granule cell numbers. Analysis of bromodeoxyuridine incorporation revealed that a 15 min pulsed treatment with 10 pM 17β-E2 increased mitogenesis, whereas continuous exposure to the same concentration of 17β-E2 was anti-mitotic. Estradiol did not increase caspase activity; however, significant increases in cellular permeability and lysis were observed. Cell lysis and death were independent of the pan-caspase inhibitor zVAD-fmk but were blocked fully by the irreversible calpain inhibitor PD150606. These results indicate that rapid activation of the ERK1/2 MAPK pathway by low concentrations of 17β-E2 induces oncotic/necrotic, but not apoptotic, programmed cell death in a subpopulation of developing granule cells and increased mitogenesis of the granule cell neuroblasts refractory to estrogen-induced neurotoxicity.",
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T1 - Estrogens and ICI182,780 (Faslodex) modulate mitosis and cell death in immature cerebellar neurons via rapid activation of p44/p42 mitogen-activated protein kinase

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AU - Zsarnovszky, A.

AU - Belcher, Scott M.

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AB - Estrogen influences the development and function of the nervous system through estrogen receptor-dependent changes in gene expression and by rapidly influencing diverse intracellular signaling pathways. We have investigated the influence of estradiol on developing neonatal rat cerebellar neurons in primary culture and found that low concentrations of 17β-estradiol (17β-E2), 17α-E2, 17β-E2-BSA, and ICI182,780 stimulated phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) mitogen-activated protein kinases (MAPK). Neither testosterone nor progesterone increased ERK1/2 phosphorylation. The effects of the estrogens were specific to the ERK1/2 MAPK pathway and were blocked by U0126, an inhibitor of the ERK1/2 MAPK kinase (MEK1/2). Compared with control cultures, significant MAPK-dependent decreases in viable granule cell numbers were observed in dissociated explant cultures of developing cerebellar neurons 24-96 hr after pulse treatment with 10 pM 17β-E2 or 10 nM ICI182,780. In contrast, continuous exposure to 10 pM 17β-E2 significantly increased granule cell numbers. Analysis of bromodeoxyuridine incorporation revealed that a 15 min pulsed treatment with 10 pM 17β-E2 increased mitogenesis, whereas continuous exposure to the same concentration of 17β-E2 was anti-mitotic. Estradiol did not increase caspase activity; however, significant increases in cellular permeability and lysis were observed. Cell lysis and death were independent of the pan-caspase inhibitor zVAD-fmk but were blocked fully by the irreversible calpain inhibitor PD150606. These results indicate that rapid activation of the ERK1/2 MAPK pathway by low concentrations of 17β-E2 induces oncotic/necrotic, but not apoptotic, programmed cell death in a subpopulation of developing granule cells and increased mitogenesis of the granule cell neuroblasts refractory to estrogen-induced neurotoxicity.

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KW - Neuron

KW - Neurotoxicity

KW - Oncosis

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