Activation of membrane estrogen receptors induce pro-survival kinases.
Experimental and epidemiological data suggest a neuroprotective role for estrogen (E(2)). We have recently shown that, in PC12 cells, non-permeable estradiol conjugated to bovine serum albumin (BSA) prevent serum-deprivation induced apoptosis through activation of specific membrane estrogen receptors (mER). In the present study, we explored in detail the early signaling events involved in this anti-apoptotic action, downstream to activation of mER. Our findings suggest that mER is associated to G-proteins, and its activation with non-permeable E(2)-BSA results in the activation of the following downstream pro-survival kinases pathways: (1) the PKB/Akt pathway, (2) the Src-->MEK-->ERK kinases and finally (3) the MAPK-->ERK kinases. Activation of these pro-survival signals leads to CREB phosphorylation and NFkappaB nuclear translocation, two transcription factors controlling the expression of anti-apoptotic Bcl-2 proteins. These data suggest that major pro-survival kinases are involved in the mER-mediated anti-apoptotic effects of estrogen. This is further supported by experiments with specific kinases inhibitors, which partially but significantly reversed the mER-mediated anti-apoptotic effect of E(2)-BSA. Our findings suggest that estrogen act via mER as potent cytoprotective factors, downstream activating pro-survival kinases, assuring thus an efficient and multipotent activation of the anti-apoptotic machinery.
Alexaki
Vasilia-Ismini
VI
Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, Heraklion 71003, Greece.
Charalampopoulos
Ioannis
I
Kampa
Marilena
M
Nifli
Artemissia-Phoebe
AP
Hatzoglou
Anastassia
A
Gravanis
Achille
A
Castanas
Elias
E
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D019001:Nitric Oxide Synthase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D017362:Cyclic AMP Response Element-Binding Protein; D004967:Estrogens; D019204:GTP-Binding Proteins; D020930:MAP Kinase Kinase Kinases; D019001:Nitric Oxide Synthase; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D012710:Serum Albumin, Bovine; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases; D000097782:NF-kappaB-Inducing Kinase