Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons

Abstract

Estrogen replacement therapy in menopausal women has been suggested to be beneficial in preventing the progression of cognitive impairment in Alzheimer disease. We demonstrated previously that the phosphatidylinositol 3-kinase (PI3-K)/Akt signal transduction pathway plays a pivotal role on the neuroprotection provided by 17beta-estradiol against acute glutamate toxicity. In the present study, we investigated the mechanism of neuroprotection against apoptosis because acute glutamate toxicity predominantly induced necrosis. 17beta-estradiol provided neuroprotection against apoptosis induced by staurosporine. This neuroprotection was inhibited by pretreatment with a PI3-K inhibitor, LY294002. An estrogen receptor specific antagonist, ICI182780, also suppressed the neuroprotection provided by 17beta-estradiol. Western blotting analysis demonstrated that treatment with 17beta-estradiol induced the phosphorylation of Akt within 5 min, which was suppressed by pretreatment with LY294002 and ICI182780. Furthermore, 17beta-estradiol induced phosphorylation of the cAMP response element binding protein (CREB) at Ser(133) within 15 min and then upregulated Bcl-2 in a PI3-K/Akt-dependent manner. Because CREB is known to be a transcription factor for Bcl-2, these results suggest that 17beta-estradiol exerts its antiapoptotic effects by CREB phosphorylation and Bcl-2 upregulation via nongenomic activation of the PI3-K/Akt pathway in cultured cortical neurons.

Nongenomic Steroid Action: Controversies, Questions, and Answers

“…The rapid time course, an effect was seen within 5 min, suggests a nongenomic response. In contrast to the study mentioned above, the ER antagonist ICI 182780 attenuated the phosphorylation of PI 3-kinase/Akt, indicating an involvement of ER in this effect (214). A direct interaction of the ER with the regulatory subunit of PI 3-kinase in endothelial cells was already shown earlier (451), and linking the ER to the PI 3-kinase pathway suggests that the ER may be involved in critical functions outside the nucleus.…”

Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against β-Amyloid Peptide-Induced Neuronal Death

“…This "E2 maintenance pathway" (Fig. 10) appears to be ER dependent, but it is unclear whether the mechanism involves predominantly classic genomic pathways (i.e., interaction of activated ER with estrogen response elements on target genes) (Pike, 1999;Perillo et al, 2000) and/or indirect genomic pathways activated by cell signaling pathways [e.g., CREB (cAMP response elementbinding protein) signaling] (Honda et al, 2001;Wu et al, 2005). Although activation of JNK signaling is linked to regulation of Bcl-2 family members (Harris and Johnson, 2001;Bae and Song, 2003), our data do not implicate JNK signaling in the E2 maintenance pathway, because under basal conditions E2 did not affect JNK phosphorylation and JNK inhibition did not affect E2 regulation of Bcl-w and Bim.…”

“…Interestingly, despite significantly attenuating indices of apoptosis, E2 provided only partial protection against A␤-induced cell death. Incomplete neuroprotection in primary neuron cultures is commonly observed with not only estrogen (Singer et al, 1996;Pike, 1999;Harms et al, 2001;Honda et al, 2001) but also androgens (Ahlbom et al, 2001;Hammond et al, 2001;Pike, 2001) and progesterone (Nilsen and Brinton, 2002), suggesting that sex steroid hormones act as partial modulators of neuronal apoptosis pathways. Thus, E2 may regulate Bcl-2 family members not only by an E2 maintenance pathway but also by an "E2 response pathway" (Fig.…”

Regulation of ERα-mediated transcription of Bcl-2 by PI3K-AKT crosstalk: Implications for breast cancer cell survival

“…Since the ER is involved in both long-term transcriptional regulation of genes (genomic effects) (61,62) and in immediate cytoplasmic signaling events (non-genomic effects) (63)(64)(65)(66)(67), these two functions of the ER may converge at the Bcl-2 promoter. The ER-E 2 complex upregulates Bcl-2 expression either directly by acting on EREs located within the coding region of the gene (29) or indirectly through interaction with the Sp1 protein (28).…”