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Aβ activation of SGK1 and increase in Mcl‐1 expression protects against Aβ‐induced toxicity in PC12 cells
Author(s) -
Lee Eminy H.Y.,
Hsu Wei L.,
Wang Ling D.,
Chiu Tsai C.,
Tai Derek J. C.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.290
Subject(s) - viability assay , toxicity , phosphorylation , microbiology and biotechnology , programmed cell death , apoptosis , kinase , sgk1 , chemistry , downregulation and upregulation , cancer research , biology , biochemistry , gene , organic chemistry
The presence of senile plaques (SP) is a major pathological hallmark of Alzheimer's disease. A major component of SP is the β‐amyloid peptide (Aβ 1 − 42 ). Aβ accumulation is central to the pathogenesis of AD by triggering free radical production and lipid peroxidation that causes progressive neuronal degeneration. While most of the research focuses on the mechanism of Aβ toxicity, it is conceivable that cells would also develop defense mechanisms to protect against Aβ toxicity. PC12 cells were used to address this issue. Results revealed that Aβ produced a dose‐dependent decrease of cell viability (0.01 to 1.0 μM) and a dose‐dependent increase in the expression of the anti‐apoptotic gene Mcl‐1. At higher doses of Aβ that cause more cell death, increase in Mcl‐1 expression was not observed. Meanwhile, Aβ (0.1 μM) increased the phosphorylation of protein kinase SGK1 at Ser78, but not at Thr256 and Ser422. Overexpression of the constitutively active SGK1, SGKS78D, increased cell viability and the expression of Mcl‐1. Overexpression of Mcl‐1 under A also increases cell viability in a dose‐dependent manner. But overexpression of the dominant negative SGK1, SGKS78A, blocked Aβ‐induced Mcl‐1 expression. These results suggest that when Aβ produces toxicity, it also triggers a defense mechanism through activation of SGK1 at Ser78 that leads to Mcl‐1 expression.