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PMID:15746252

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Citation

Dhandapani, KM, Wade, FM, Mahesh, VB and Brann, DW (2005) Astrocyte-derived transforming growth factor-{beta} mediates the neuroprotective effects of 17{beta}-estradiol: involvement of nonclassical genomic signaling pathways. Endocrinology 146:2749-59

Abstract

17beta-Estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen, mediate numerous effects in the brain, including neurosecretion, neuroprotection, and the induction of synaptic plasticity. Astrocytes, the most abundant cell type in the brain, influence many of these same functions and thus may represent a mediator of estrogen action. The present study examined the regulatory effect and underlying cell signaling mechanisms of E2-induced release of neurotropic growth factors from primary rat cortical astrocyte cultures. The results revealed that E2 (0.5, 1, and 10 nm) and tamoxifen (1 mum) increased both the expression and release of the neuroprotective cytokines, TGF-beta1 and TGF-beta2 (TGF-beta), from cortical astrocytes. The stimulatory effect of E2 was attenuated by the estrogen receptor (ER) antagonist, ICI182,780, suggesting ER dependency. The effect of E2 also appeared to involve mediation by the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway, because E2 rapidly induced Akt phosphorylation, and pharmacological or molecular inhibition of the PI3K/Akt pathway prevented E2-induced release of TGF-beta. Additionally, the membrane-impermeant conjugate, E2-BSA, stimulated the release of TGF-beta, suggesting the potential involvement of a membrane-bound ER. Finally, E2, tamoxifen, and E2-BSA were shown to protect neuronal-astrocyte cocultures from camptothecin-induced neuronal cell death, effects that were attenuated by ICI182,780, Akt inhibition, or TGF-beta immunoneutralization. As a whole, these studies suggest that E2 induction of TGF-beta release from cortical astrocytes could provide a mechanism of neuroprotection, and that E2 stimulation of TGF-beta expression and release from astrocytes occurs via an ER-dependent mechanism involving mediation by the PI3K/Akt signaling pathway.

Links

PubMed Online version:10.1210/en.2005-0014

Keywords

Animals; Astrocytes/cytology; Astrocytes/metabolism; Cell Line; Cerebral Cortex/cytology; Estradiol/pharmacology; Gene Expression/drug effects; Neuroprotective Agents/pharmacology; Phosphatidylinositol 3-Kinases/metabolism; Phosphorylation/drug effects; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Estrogen/genetics; Receptors, Estrogen/metabolism; Selective Estrogen Receptor Modulators/pharmacology; Signal Transduction/drug effects; Signal Transduction/physiology; Tamoxifen/pharmacology; Transforming Growth Factor beta/genetics; Transforming Growth Factor beta/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:TGFB2

involved_in

GO:0032355: response to estradiol

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:TGFB2

involved_in

GO:0009410: response to xenobiotic stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:TGFB1

involved_in

GO:0032355: response to estradiol

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:TGFB1

involved_in

GO:0014070: response to organic cyclic compound

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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