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β-Amyloid-evoked apoptotic cell death is mediated through MKK6-p66shc pathway.

Authors
  • Bashir, Muneesa
  • Parray, Arif A
  • Baba, Rafia A
  • Bhat, Hina F
  • Bhat, Sehar S
  • Mushtaq, Umar
  • Andrabi, Khurshid I
  • Khanday, Firdous A
Type
Published Article
Journal
NeuroMolecular Medicine
Publisher
Springer-Verlag
Publication Date
Mar 01, 2014
Volume
16
Issue
1
Pages
137–149
Identifiers
DOI: 10.1007/s12017-013-8268-4
PMID: 24085465
Source
Medline
License
Unknown

Abstract

We have previously shown the involvement of p66shc in mediating apoptosis. Here, we demonstrate the novel mechanism of β-Amyloid-induced toxicity in the mammalian cells. β-Amyloid leads to the phosphorylation of p66shc at the serine 36 residue and activates MKK6, by mediating the phosphorylation at serine 207 residue. Treatment of cells with antioxidants blocks β-Amyloid-induced serine phosphorylation of MKK6, reactive oxygen species (ROS) generation, and hence protected cells against β-Amyloid-induced cell death. Our results indicate that serine phosphorylation of p66shc is carried out by active MKK6. MKK6 knock-down resulted in decreased serine 36 phosphorylation of p66shc. Co-immunoprecipitation results demonstrate a direct physical association between p66shc and WT MKK6, but not with its mutants. Increase in β-Amyloid-induced ROS production was observed in the presence of MKK6 and p66shc, when compared to triple mutant of MKK6 (inactive) and S36 mutant of p66shc. ROS scavengers and knock-down against p66shc, and MKK6 significantly decreased the endogenous level of active p66shc, ROS production, and cell death. Finally, we show that the MKK6-p66shc complex mediates β-Amyloid-evoked apoptotic cell death.

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