title: Oxidative stress stimulates apoptosis and activates NF-kappaB in osteoblastic cells via a PKCbeta/p66shc signaling cascade: counter regulation by estrogens or androgens.
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 p66(shc), a redox enzyme that amplifies mitochondrial reactive oxygen species generation and stimulates apoptosis. We report that in mesenchymal progenitor and osteoblastic cell models, H(2)O(2) activated a protein kinase C (PKC)β/p66(shc)/NF-κB signaling cascade and that p66(shc) was an essential mediator of the stimulating effects of H(2)O(2) on the apoptosis of osteoblastic cells as well as their ability to activate NF-κB. 17β-Estradiol (E(2)) or the nonaromatizable androgen dihydrotestosterone abrogated the effects of H(2)O(2) on p66(shc) and NF-κB activation by attenuating the phosphorylation of the redox-sensitive cytoplasmic kinase PKCβ. Additionally, both E(2) and dihydrotestosterone prevented H(2)O(2)-induced apoptosis by a mechanism that involved attenuation of p66(shc) resulting from decreased phosphorylation of PKCβ. Consistent with a kinase-mediated mechanism of sex steroid action, the effects of E(2) were reproduced by a polymeric form of estradiol that is not capable of stimulating the nuclear-initiated actions of ERα. These results demonstrate that p66(shc) 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 p66(shc) phosphorylation via a mechanism that does not require stimulation of the nuclear-initiated actions of sex steroids.
authors.affiliation: University of Arkansas for Medical Sciences, Division of Endocrinology and Metabolism, Little Rock, Arkansas 72205-7199, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.forename: Elena
authors.initials: E
authors.lastname: Ambrogini
authors.forename: Shoshana M
authors.initials: SM
authors.lastname: Bartell
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D000728:Androgens; D004967:Estrogens; D016328:NF-kappa B; D016877:Oxidants; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D064546:Protein Kinase C beta