Neurosteroid dehydroepiandrosterone exerts anti-apoptotic effects by membrane-mediated, integrated genomic and non-genomic pro-survival signaling pathways
In: Journal of neurochemistry, Jg. 107 (2008), Heft 5, S. 1457-1469
Online
academicJournal
- print, 1 p.1/2
Zugriff:
Dehydroepiandrosterone (DHEA) protects neural crest-derived PC12 cells from serum deprivation-induced apoptosis via G protein-associated specific plasma membrane-binding sites (mDBS). Here, we studied the signaling pathways involved in the pro-survival effects of DHEA-mediated activation of the mDBS binding sites. Membrane impermeable DHEA-bovine serum albumin (BSA) conjugate induced an acute phosphorylation of the prosurvival kinases Src, protein kinase A (PKA), MEK1/2/ERK1/2, and PI3K/Akt in serum deprived PC12 cells in parallel to an elevation of intracellular cAMP. The physiological significance of these findings was further assessed in a series of experiments using several selective pro-survival kinase inhibitors. Our combined findings suggest that the following sequence of events may take place following activation of mDBS binding sites: DHEA-BSA induces an acute but transient sequential phosphorylation of the pro-survival kinases Src/PKCa/b/MEK1/2/ERK1/2 which, in their turn, activate transcription factors cAMP responsive element binding protein and nuclear factor kappa B which induce the expression of the anti-apoptotic Bcl-2 genes. In parallel, DHEA-BSA increases intracellular cAMP, and the subsequent phosphorylation of PKA kinase and of cAMP responsive element binding protein. Finally, DHEA-BSA induces phosphorylation of PI3K/Akt kinases which, subsequently, lead to phosphorylation/deactivation of the pro-apoptotic Bad. Our findings suggest that the neurosteroid DHEA affects neural crest-derived cell survival by multiple pro-survival signaling pathways comprising an integrated system of non-genomic and genomic mechanisms.
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Neurosteroid dehydroepiandrosterone exerts anti-apoptotic effects by membrane-mediated, integrated genomic and non-genomic pro-survival signaling pathways
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Autor/in / Beteiligte Person: | CHARALAMPOPOULOS, Loannis ; MARGIORIS, Andrew N ; GRAVANIS, Achille |
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Zeitschrift: | Journal of neurochemistry, Jg. 107 (2008), Heft 5, S. 1457-1469 |
Veröffentlichung: | Oxford: Blackwell, 2008 |
Medientyp: | academicJournal |
Umfang: | print, 1 p.1/2 |
ISSN: | 0022-3042 (print) |
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