The Amyloid Precursor Protein Potentiates CHOP Induction and Cell Death in Response to ER Ca2+ Depletion

Biochim Biophys Acta. 2007 Feb;1773(2):157-65. doi: 10.1016/j.bbamcr.2006.10.002. Epub 2006 Oct 19.

Abstract

Here we investigated the role of the amyloid precursor protein (APP) in regulation of Ca(2+) store depletion-induced neural cell death. Ca(2+) store depletion from the endoplasmic reticulum (ER) was induced by the SERCA (Sarco/Endoplasmic Reticulum Calcium ATPase) inhibitor thapsigargin which led to a rapid induction of the unfolded protein response (UPR) and a delayed activation of executioner caspases in the cultures. Overexpression of APP potently enhanced cytosolic Ca(2+) levels and cell death after ER Ca(2+) store depletion in comparison to vector-transfected controls. GeneChip and RT-PCR analysis revealed that the expression of classical UPR chaperone genes was not altered by overexpression of APP. Interestingly, the induction of the ER stress-responsive pro-apoptotic transcription factor CHOP was significantly upregulated in APP-overexpressing cells in comparison to vector-transfected controls. Chelation of intracellular Ca(2+) with BAPTA-AM revealed that enhanced CHOP expression after store depletion occurred in a Ca(2+)-dependent manner in APP-overexpressing cells. Prevention of CHOP induction by BAPTA-AM and by RNA interference was also able to abrogate the potentiating effect of APP on thapsigargin-induced apoptosis. Application of the store-operated channel (SOC)-inhibitors SK & F96365 and 2-APB downmodulated APP-triggered potentiation of cytosolic Ca(2+) levels and apoptosis after treatment with thapsigargin. Our data demonstrate that APP significantly modulates Ca(2+) store depletion-induced cell death in a SOC- and CHOP-dependent manner, but independent of the UPR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Buffers
  • Calcium / deficiency*
  • Calcium Channels / metabolism
  • Cell Death / drug effects
  • Chelating Agents / pharmacology
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Gene Expression Regulation* / drug effects
  • Humans
  • Ion Channel Gating / drug effects
  • PC12 Cells
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Thapsigargin / pharmacology
  • Transcription Factor CHOP / deficiency
  • Transcription Factor CHOP / genetics*
  • Transcription Factor CHOP / metabolism*
  • Transcription, Genetic / drug effects

Substances

  • Amyloid beta-Protein Precursor
  • Buffers
  • Calcium Channels
  • Chelating Agents
  • RNA, Messenger
  • Transcription Factor CHOP
  • Egtazic Acid
  • Thapsigargin
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
  • Calcium