A mathematical model of the hsp70 regulation in the cell.

A mathematical model of the regulation process of the heat shock protein hsp70 in the cell is presented. The model describes the damaging effect of elevated temperature on proteins; the interaction of free hsp70 with injured proteins and its chaperone role in nascent protein translation; the relation between the amount of free hsp70 and the formation of the activated trimer form of the heat shock factor protein (HSF); the binding of activated HSF with the heat shock elements on the DNA; the transcription of mRNA of hsp70 and the synthesis of hsp70. The reaction of the model to a temporal rise in temperature shows an initial decline and a subsequent sharp rise to an ultimately increased level of free hsp70 in the cell. The response of the model to both a single and two consecutive heat shocks appears to closely resemble experimental data on hsp70 synthesis. This general agreement demonstrates the structure of the model to be sound and suitable as a basis for further modelling the complex tolerance mechanism of the cell.

[1]  M. Lovett,et al.  Examining the function and regulation of hsp 70 in cells subjected to metabolic stress , 1992, The Journal of cell biology.

[2]  R. Morimoto,et al.  The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression. , 1992, Genes & development.

[3]  Peter K. Sorger,et al.  Heat shock factor is regulated differently in yeast and HeLa cells , 1987, Nature.

[4]  I. Dawid,et al.  Purification and properties of Drosophila heat shock activator protein. , 1987, Science.

[5]  S. Lindquist,et al.  The heat shock response is self-regulated at both the transcriptional and posttranscriptional levels , 1982, Cell.

[6]  G. Li,et al.  Re-induction of hsp70 synthesis: an assay for thermotolerance. , 1989, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[7]  R. Morimoto,et al.  Transcriptional regulation of heat shock genes. A paradigm for inducible genomic responses. , 1992, The Journal of biological chemistry.

[8]  W. Welch,et al.  Characterization of the thermotolerant cell. I. Effects on protein synthesis activity and the regulation of heat-shock protein 70 expression , 1988, The Journal of cell biology.

[9]  Harold Chestnut,et al.  Servomechanisms and regulating system design , 1951 .

[10]  R. van Wijk,et al.  Stressor-specific activation of heat shock genes in H35 rat hepatoma cells. , 1995, Toxicology and applied pharmacology.

[11]  F. Hartl.  Protein Folding In The Cell: The Role Of Molecular Chaperones , 1996 .

[12]  A. Nussenzweig,et al.  Modulation of thermal induction of hsp70 expression by Ku autoantigen or its individual subunits , 1996, Molecular and cellular biology.

[13]  L. Nover.  Heat Shock Response , 1991 .

[14]  C. Georgopoulos,et al.  Role of the major heat shock proteins as molecular chaperones. , 1993, Annual review of cell biology.

[15]  R. Morimoto,et al.  Cells in stress: transcriptional activation of heat shock genes. , 1993, Science.

[16]  W. Welch,et al.  Interaction of Hsp 70 with newly synthesized proteins: implications for protein folding and assembly. , 1990, Science.

[17]  Carl Wu.  Two protein-binding sites in chromatin implicated in the activation of heat-shock genes , 1984, Nature.

[18]  C. Gross,et al.  Is hsp70 the cellular thermometer? , 1991, Trends in biochemical sciences.

[19]  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.

[20]  C. Grimbergen,et al.  An approach to the modeling of the tolerance mechanism in the drug effect. II: On the implications of compensatory regulation. , 1988, Journal of theoretical biology.

[21]  D. Cavener,et al.  Heat shock effects on phosphorylation of protein synthesis initiation factor proteins eIF-4E and eIF-2 alpha in Drosophila. , 1995, Biochemistry.

[22]  J. Hershey,et al.  Heat shock-induced translational alterations in HeLa cells. Initiation factor modifications and the inhibition of translation. , 1984, The Journal of biological chemistry.

[23]  R. Morimoto,et al.  Posttranscriptional regulation of hsp70 expression in human cells: effects of heat shock, inhibition of protein synthesis, and adenovirus infection on translation and mRNA stability , 1987, Molecular and cellular biology.

[24]  B. Hall.  Yeast thermotolerance does not require protein synthesis , 1983, Journal of bacteriology.

[25]  R. van Wijk,et al.  Hepatoma cells adapted to proliferate under normally lethal hyperthermic stress conditions show rapid decay of thermoresistance and heat shock protein synthesis when returned to 37 degrees C. , 1995, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[26]  B. Bukau,et al.  Conserved ATPase and luciferase refolding activities between bacteria and yeast Hsp70 chaperones and modulators , 1995, FEBS letters.

[27]  G. Li,et al.  Thermal response of rat fibroblasts stably transfected with the human 70-kDa heat shock protein-encoding gene. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[28]  G. Hahn,et al.  Analysis of HSF-1 phosphorylation in A549 cells treated with a variety of stresses. , 1994, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[29]  S. Lindquist.  The heat-shock response. , 1986, Annual review of biochemistry.

[30]  E. K. Boon-Niermeijer,et al.  Evidence for two states of thermotolerance. , 1986, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[31]  R. Baler,et al.  Heat shock gene regulation by nascent polypeptides and denatured proteins: hsp70 as a potential autoregulatory factor , 1992, The Journal of cell biology.

[32]  Judith Frydman,et al.  Folding of nascent polypeptide chains in a high molecular mass assembly with molecular chaperones , 1994, Nature.

[33]  J. Sambrook,et al.  Protein folding in the cell , 1992, Nature.

[34]  J R Subjeck,et al.  Stress protein systems of mammalian cells. , 1986, The American journal of physiology.

[35]  Z. Xu,et al.  Denatured proteins inhibit translation in hemin-supplemented rabbit reticulocyte lysate by inducing the activation of the heme-regulated eIF-2 alpha kinase. , 1993, Biochemistry.

[36]  S. Lindquist,et al.  Heat shock and recovery are mediated by different translational mechanisms. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[37]  M. Werner-Washburne,et al.  The translation machinery and 70 kd heat shock protein cooperate in protein synthesis , 1992, Cell.

[38]  W. Welch,et al.  Complex environment of nascent polypeptide chains. , 1994, The Journal of biological chemistry.

[39]  S. Penman,et al.  Regulation of protein synthesis in HeLa cells: translation at elevated temperatures. , 1969, Journal of molecular biology.

[40]  J. Lepock,et al.  Thermal analysis of CHL V79 cells using differential scanning calorimetry: Implications for hyperthermic cell killing and the heat shock response , 1988, Journal of cellular physiology.

[41]  Peter K. Sorger,et al.  Heat shock factor and the heat shock response , 1991, Cell.

[42]  R. Kingston.  CHAPTER 18 - Transcriptional regulation of heat shock genes , 1991 .

[43]  F. Hartl,et al.  Protein folding in the cell: the role of molecular chaperones Hsp70 and Hsp60. , 1992, Annual review of biophysics and biomolecular structure.

[44]  J. Hershey,et al.  Protein synthesis and protein phosphorylation during heat stress, recovery, and adaptation , 1989, The Journal of cell biology.

[45]  C. Grimbergen,et al.  An approach to the modeling of the tolerance mechanism in the drug effect. I: The drug effect as a disturbance of regulations. , 1987, Journal of theoretical biology.

[46]  A. Laszlo.  Evidence for two states of thermotolerance in mammalian cells. , 1988, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[47]  R. Morimoto,et al.  The human cytosolic molecular chaperones hsp90, hsp70 (hsc70) and hdj‐1 have distinct roles in recognition of a non‐native protein and protein refolding. , 1996, The EMBO journal.

[48]  D. D. Mosser,et al.  The DNA-binding activity of the human heat shock transcription factor is regulated in vivo by hsp70 , 1993, Molecular and cellular biology.

[49]  R. Cohen,et al.  Periodic interactions of heat shock transcriptional elements , 1988, Nature.

[50]  R. Morimoto,et al.  Stress proteins in biology and medicine , 1991 .

[51]  R. van Wijk,et al.  Modulation of HSP68 gene expression after heat shock in thermosensitized and thermotolerant cells is not solely regulated by binding of HSF to HSE. , 1995, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[52]  H. Xiao,et al.  Germline transformation used to define key features of heat-shock response elements. , 1988, Science.

[53]  J. Mak,et al.  Stable Expression of Human HSP70 Gene in Rodent Cells Confers Thermal Resistance , 1991 .

[54]  R. van Wijk,et al.  Thermotolerance in cultured hepatoma cells: cell viability, cell morphology, protein synthesis, and heat-shock proteins. , 1984, Radiation research.

[55]  M. Morange,et al.  Protein denaturation during heat shock and related stress. Escherichia coli beta-galactosidase and Photinus pyralis luciferase inactivation in mouse cells. , 1989, The Journal of biological chemistry.

[56]  W. Welch,et al.  Nuclear and nucleolar localization of the 72,000-dalton heat shock protein in heat-shocked mammalian cells. , 1984, The Journal of biological chemistry.

[57]  L. Hightower,et al.  Thermal activation of the bovine Hsc70 molecular chaperone at physiological temperatures: physical evidence of a molecular thermometer. , 1996, Cell stress & chaperones.

[58]  K. Riabowol,et al.  Heat shock is lethal to fibroblasts microinjected with antibodies against hsp70. , 1988, Science.

[59]  R. Kingston,et al.  Human HSP70 promoter contains at least two distinct regulatory domains. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[60]  R. Morimoto,et al.  Identification of a regulatory motif in Hsp70 that affects ATPase activity, substrate binding and interaction with HDJ‐1. , 1995, The EMBO journal.

[61]  N. Marceau,et al.  Synthesis and degradation of heat shock proteins during development and decay of thermotolerance. , 1982, Cancer research.

[62]  E. Craig,et al.  Transcriptional regulation of SSA3, an HSP70 gene from Saccharomyces cerevisiae , 1990, Molecular and cellular biology.

[63]  C. S. Parker,et al.  Sequences required for in vitro transcriptional activation of a Drosophila hsp 70 gene , 1985, Cell.

[64]  L. Aujame,et al.  The major inducible heat shock protein hsp68 is not required for acquisition of thermal resistance in mouse plasmacytoma cell lines , 1988, Molecular and cellular biology.

[65]  R. van Wijk,et al.  Heat-induced unresponsiveness of heat shock gene expression is regulated at the transcriptional level. , 1993, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[66]  R. van Wijk,et al.  Thermotolerance induced by heat and ethanol. , 1988, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[67]  L. Weber,et al.  Modulation of heat-shock polypeptide synthesis in HeLa cells during hyperthermia and recovery. , 1982, Biochemistry.

[68]  R. Morimoto,et al.  Transcription and post-transcriptional regulation of avian HSP70 gene expression. , 1986, The Journal of biological chemistry.

[69]  L. Weinberg,et al.  Automatic Feedback Control System Synthesis , 1956 .

[70]  R. van Wijk,et al.  Temperature-dependency of the expression of heat shock proteins in rat hepatoma cells with a different degree of heat sensitivity. , 1993, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.