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Neurosteroid dehydroepiandrosterone exerts anti‐apoptotic effects by membrane‐mediated, integrated genomic and non‐genomic pro‐survival signaling pathways
Author(s) -
Charalampopoulos Ioannis,
Margioris Andrew N.,
Gravanis Achille
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05732.x
Subject(s) - protein kinase b , phosphorylation , protein kinase a , kinase , biology , microbiology and biotechnology , proto oncogene tyrosine protein kinase src , signal transduction , dehydroepiandrosterone , protein kinase c , pi3k/akt/mtor pathway , chemistry , biochemistry , hormone , androgen
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/PKC a/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.