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Biochemical and Molecular Actions of Nutrients

1,25-Dihydroxycholecalciferol Inhibits Apoptosis in C3H10T1/2 Murine Fibroblast Cells Through Activation of Nuclear Factor B¹

Department of Foods and Nutrition, Purdue University, West, Lafayette, IN 47907

²To whom correspondence should be addressed. E-mail: Teegarden{at}cfs.purdue.edu.

1,25-dihydroxycholecalciferol [1,25(OH)₂D₃] is important in the regulation of cell growth, differentiation, and apoptosis. Previous results from our laboratory demonstrate that 1,25(OH)₂D₃ inhibits vitamin E succinate (VES) mediated apoptosis in untransformed C3H10T1/2 mouse fibroblast cells. The current work investigated cell survival signaling pathways that may be activated by 1,25(OH)₂D₃, leading to protection from apoptosis. Results showed that nuclear factor B (NFB) transcriptional activity was significantly increased 1.8-fold over vehicle controls by 1,25(OH)₂D₃ after 4 h of treatment. Protein kinase B/AKT, a downstream effector of phosphoinositide 3-kinase (PI3K), was activated 4-fold and 8-fold at 2 and 4 h, respectively, after treatment with 1,25(OH)₂D₃. Pretreatment with two PI3K inhibitors, LY294002 and wortmannin, abolished the activation of NFB by 1,25(OH)₂D₃, suggesting that this pathway is essential for NFB transcriptional activation. Additionally, the use of a p-21 activated kinase (PAK1) inhibitory construct (PAK^R299) demonstrated that PAK1 was also required for NFB transcriptional activation by 1,25(OH)₂D₃. Inhibition of NFB activity with transfection of the NFB inhibitory construct (IB^Ala32) abolished the protective effect of 1,25(OH)₂D₃ on VES-mediated apoptosis. In summary, NFB transcriptional activation was essential to 1,25(OH)₂D₃ protection from VES-mediated apoptosis and 1,25(OH)₂D₃ regulated NFB activity through PI3K and PAK pathways.

KEY WORDS: • 1,25-dihydroxycholecalciferol • p21 activated kinase • nuclear factor B • phosphoinositide-3-kinase • C3H10T1/2 cells

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