A novel defense mechanism that is activated on amyloid-β insult to mediate cell survival: role of SGK1-STAT1/STAT2 signaling

• Published in: Cell death and differentiation Vol. 16; no. 11; pp. 1515 - 1529
• Main Authors: Hsu, W L, Chiu, T H, Tai, D J C, Ma, Y L, Lee, E H Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2009
• Subjects: Amino Acid Substitution; Amyloid beta-Peptides - pharmacology; Animals; Apoptosis; Base Sequence; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell Survival; Immediate-Early Proteins - metabolism; Immediate-Early Proteins - physiology; Life Sciences; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular Sequence Data; Myeloid Cell Leukemia Sequence 1 Protein; original-paper; PC12 Cells; Peptide Fragments - pharmacology; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; RNA, Small Interfering - metabolism; Signal Transduction; STAT1 Transcription Factor - metabolism; STAT2 Transcription Factor - metabolism; Stem Cells; Transfection; A; Mcl-1; anti-apoptosis; ERK1/2; STAT1; STAT2; SGK1
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2009.91

Amyloid- β (A β ) is known to induce apoptotic cell death and its underlying mechanism has been studied extensively, but the endogenous protection mechanism that results from A β insult is less known. In this study, we have found that A β 1−42 produced a dose-dependent decrease in cell viability and dose-dependent increase in apoptotic cell death in PC12 cells. Meanwhile, A β 1−42 (0.1  μ M) increased the phosphorylation of serum- and glucocorticoid-inducible kinase1 (SGK1) at Ser-78 specifically. A parallel increase in ERK1/2, STAT1 and STAT2 phosphorylation and the anti-apoptotic gene Mcl-1 expression was also observed. Transfection of rat siRNAs against ERK1/2, SGK1, STAT1 and STAT2 abolished these effects of A β . Transfection of sgkS78D , the constitutively active SGK1, dose-dependently protected against A β -induced apoptosis and dose-dependently increased the expression of Mcl-1. SGK1 activation further phosphorylates STAT1 at Tyr-701 and Ser-727 directly, and activates STAT2 at Tyr-690 indirectly. Phosphorylation of STAT1/STAT2 upregulated Mcl-1 expression which in turn protected against A β -induced apoptosis. But Mcl-1 siRNA transfection enhanced A β -induced apoptosis. Mutation of SGK1 at Ser-78 blocked the effect of A β on STAT1/STAT2 phosphorylation and Mcl-1 expression. Further, mutation of STAT1/STAT2 prevented the effect of both A β and SGK1 on Mcl-1 expression. These results together showed a novel endogenous protection mechanism that is activated on A β insult to mediate cell survival.