蛋白激酶C
生物
细胞生物学
氧化应激
信号转导
磷酸化
细胞凋亡
活性氧
内分泌学
内科学
生物化学
医学
作者
Maria Almeida,Han Li,Elena Ambrogini,Shoshana M. Bartell,Stavros C. Manolagas
摘要
Abstract Aging or acute loss of estrogens or androgens increases the levels of reactive oxygen species, activates nuclear factor-κB (NF-κB), and promotes the phosphorylation of p66shc, a redox enzyme that amplifies mitochondrial reactive oxygen species generation and stimulates apoptosis. We report that in mesenchymal progenitor and osteoblastic cell models, H2O2 activated a protein kinase C (PKC)β/p66shc/NF-κB signaling cascade and that p66shc was an essential mediator of the stimulating effects of H2O2 on the apoptosis of osteoblastic cells as well as their ability to activate NF-κB. 17β-Estradiol (E2) or the nonaromatizable androgen dihydrotestosterone abrogated the effects of H2O2 on p66shc and NF-κB activation by attenuating the phosphorylation of the redox-sensitive cytoplasmic kinase PKCβ. Additionally, both E2 and dihydrotestosterone prevented H2O2-induced apoptosis by a mechanism that involved attenuation of p66shc resulting from decreased phosphorylation of PKCβ. Consistent with a kinase-mediated mechanism of sex steroid action, the effects of E2 were reproduced by a polymeric form of estradiol that is not capable of stimulating the nuclear-initiated actions of ERα. These results demonstrate that p66shc is an essential mediator of the effects of oxidative stress on osteoblastic cell apoptosis, NF-κB activation, and cytokine production. The ability of either estrogen or androgen to attenuate the effects of oxidative stress on osteoblastic cell apoptosis, NF-κB activation, and cytokine production results from their common property to suppress PKCβ-induced p66shc phosphorylation via a mechanism that does not require stimulation of the nuclear-initiated actions of sex steroids.
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