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G protein βγ complex‐mediated apoptosis by familial Alzheimer's disease mutant of APP
Author(s) -
Giambarella Ugo,
Yamatsuji Tomoki,
Okamoto Takashi,
Matsui Takashi,
Ikezu Tsuneya,
Murayama Yoshitake,
Levine Michael A.,
Katz Arieh,
Gautam Narasimhan,
Nishimoto Ikuo
Publication year - 1997
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/16.16.4897
Subject(s) - biology , mutant , beta (programming language) , mutation , apoptosis , genetics , disease , alzheimer's disease , microbiology and biotechnology , gene , medicine , computer science , programming language
In familial Alzheimer's disease (FAD), three missense mutations, V642I, V642F and V642G, that co‐segregate with the disease phenotype have been discovered in the 695 amino acid form of the amyloid precursor protein APP. Expression of these mutants causes a COS cell NK1 clone to undergo pertussis toxin‐sensitive apoptosis in an FAD trait‐linked manner by activating the G protein G o , which consists of Gα o and Gβγ subunits. We investigated which subunit was responsible for the induction of apoptosis by V642I APP in NK1 cells. In the same system, expression of mutationally activated Gα o or Gα i induced little apoptosis. Apoptosis by V642I APP was antagonized by the overexpression of the carboxy‐terminal amino acids 495–689 of the β‐adrenergic receptor kinase‐1, which blocks the specific functions of Gβγ. Co‐transfection of Gβ2γ2 cDNAs, but not that of other Gβxγz (x = 1–3; z = 2, 3), induced DNA fragmentation in a manner sensitive to bcl‐2. These data implicate Gβγ as a cell death mediator for the FAD‐associated mutant of APP.