Thermotolerance and cell death are distinct cellular responses to stress: dependence on heat shock proteins

We tested the hypothesis that heat shock protein (Hsp) induction and cell death are mutually exclusive responses to stress. Despite activation of heat shock transcription factor 1 at temperatures ranging from 40 to 46°C, Hsp72 and Hsp27 were not induced above 42°C. Moreover, cells underwent apoptosis at 44°C and necrosis at 46°C, with mitochondrial cytochrome c release at both temperatures. However, only apoptosis was associated with caspase activation. Treatment of cells with z‐VAD‐fmk prior to heat shock at 44°C failed to restore Hsp induction despite inhibition of heat‐induced apoptosis. Furthermore, accumulation of Hsps after incubation at 42°C rendered the cells resistant to apoptosis. These results suggest that lack of Hsp induction is the cause rather than the consequence of cell death.

[1]  R. Morimoto,et al.  Activation of Heat Shock Factor 1 DNA Binding Precedes Stress-induced Serine Phosphorylation , 1996, The Journal of Biological Chemistry.

[2]  S. Lindquist,et al.  The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. , 1993, Annual review of genetics.

[3]  Xiaodong Wang,et al.  Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome c , 1996, Cell.

[4]  Z. Werb,et al.  Correlation between synthesis of heat shock proteins and development of thermotolerance in Chinese hamster fibroblasts. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Qingbo Xu,et al.  Activation of Fas inhibits heat‐induced activation of HSF1 and up‐regulation of hsp70 , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  S. Lindquist,et al.  The heat-shock proteins. , 1988, Annual review of genetics.

[7]  Y. Lazebnik,et al.  Caspases: enemies within. , 1998, Science.

[8]  R. Morimoto,et al.  Regulation of the Heat Shock Transcriptional Response: Cross Talk between a Family of Heat Shock Factors, Molecular Chaperones, and Negative Regulators the Heat Shock Factor Family: Redundancy and Specialization , 2022 .

[9]  S. Orrenius,et al.  Heat shock proteins: regulators of stress response and apoptosis. , 1998, Cell stress & chaperones.

[10]  M. Jäättelä,et al.  Escaping cell death: survival proteins in cancer. , 1999, Experimental cell research.

[11]  R. Morimoto,et al.  The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones. , 1997, Essays in biochemistry.

[12]  S. Srinivasula,et al.  Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade , 1997, Cell.

[13]  P. Csermely,et al.  Mammalian Hsp70 and Hsp110 Proteins Bind to RNA Motifs Involved in mRNA Stability* , 1999, The Journal of Biological Chemistry.

[14]  M. King,et al.  The mutagenic potential of hyperthermia and fever in mice. , 1983, Mutation research.

[15]  Xiaodong Wang,et al.  Apaf-1, a Human Protein Homologous to C. elegans CED-4, Participates in Cytochrome c–Dependent Activation of Caspase-3 , 1997, Cell.

[16]  G. Kroemer,et al.  The mitochondrial death/life regulator in apoptosis and necrosis. , 1998, Annual review of physiology.

[17]  Carl Wu,et al.  Heat shock transcription factors: structure and regulation. , 1995, Annual review of cell and developmental biology.

[18]  P. Moseley,et al.  Heat shock proteins and heat adaptation of the whole organism. , 1997, Journal of applied physiology.

[19]  C. Stroh,et al.  Death by a thousand cuts: an ever increasing list of caspase substrates , 1998, Cell Death and Differentiation.

[20]  R. Morimoto,et al.  Coordinate changes in heat shock element-binding activity and HSP70 gene transcription rates in human cells. , 1988, Molecular and cellular biology.

[21]  G. Hahn,et al.  A proposed operational model of thermotolerance based on effects of nutrients and the initial treatment temperature. , 1980, Cancer research.

[22]  T G Cotter,et al.  Antioxidant‐mediated inhibition of the heat shock response leads to apoptosis , 1999, FEBS letters.

[23]  J. Subjeck,et al.  Heat shock proteins and protection of proliferation and translation in mammalian cells. , 1984, Cancer research.

[24]  R. Morimoto,et al.  Activation of Heat Shock Gene Transcription by Heat Shock Factor 1 Involves Oligomerization, Acquisition of DNA-Binding Activity, and Nuclear Localization and Can Occur in the Absence of Stress , 1993, Molecular and cellular biology.

[25]  T. Cotter,et al.  The ability to cleave 28S ribosomal RNA during apoptosis is a cell-type dependent trait unrelated to DNA fragmentation , 1997, Cell Death and Differentiation.

[26]  T G Cotter,et al.  Heat shock proteins increase resistance to apoptosis. , 1996, Experimental cell research.

[27]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[28]  D. Harrison,et al.  Apoptosis: an overview of the process and its relevance in disease. , 1997, Advances in pharmacology.

[29]  B. Zhivotovsky,et al.  Presence of a pre‐apoptotic complex of pro‐caspase‐3, Hsp60 and Hsp10 in the mitochondrial fraction of Jurkat cells , 1999, The EMBO journal.

[30]  A. Black,et al.  Involvement of rRNA synthesis in the enhanced survival and recovery of protein synthesis seen in thermotolerance , 1989, Journal of cellular physiology.