The mechanism whereby heat shock induces apoptosis depends on the innate sensitivity of cells to stress.
The cellular response to heat shock (HS) is a paradigm for many human diseases collectively known as "protein conformation diseases" in which the accumulation of misfolded proteins induces cell death. Here, we analyzed how cells having a different apoptotic threshold die subsequent to a treatment with HS. Cells with a low apoptotic threshold mainly induced apoptosis through activation of conventional stress kinase signaling pathways. By contrast, cells with a high apoptotic threshold also died by apoptosis but likely after the accumulation of heat-aggregated proteins as revealed by the formation of aggresomes in these cells, which were associated with the generation of atypical nuclear deformations. Inhibition of the proteasome or expression of an aggregation prone protein produced similar nuclear alterations. Furthermore, elevated levels of chaperones markedly suppressed both HS-induced nuclear deformations and apoptosis induced upon protein aggregation whereas they had little effect on stress kinase-mediated apoptosis. We conclude that the relative contribution of stress signaling pathways and the accumulation of protein aggregates to cell death by apoptosis is related to the innate sensitivity of cells to deadly insults.
Bellmann
Kerstin
K
Centre de recherche en cancérologie de l'Université Laval, Québec, QC, Canada.
Charette
Steve J
SJ
Nadeau
Philippe J
PJ
Poirier
Dominic J
DJ
Loranger
Anne
A
Landry
Jacques
J
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D018869:Heat-Shock Response; D006801:Humans; D000071058:Huntingtin Protein; D020935:MAP Kinase Signaling System; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013696:Temperature; D014162:Transfection
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D046988:Proteasome Endopeptidase Complex