Digital-analog hybrid control model for eukaryotic heat shock response illustrating the dynamics of heat shock protein 70 on exposure to thermal stress

We are introducing in this paper a digital-analog hybrid model approach for the study of a complete gene regulatory network; the heat shock response (HSR) network of eukaryotes. HSR is a crucial and widely studied cellular phenomenon occurring due to various stresses on the cell, and is characterised by the induction of heat shock genes resulting in the production of heat shock proteins (HSPs) which restores cellular homeostasis by maintaining protein integrity. We are proposing a model which incorporates simple digital and analog components which mimic the functioning of biological molecules involved in HSR and model their dynamics and behaviour. The simulation result of the circuit for the production of HSP70 has been found to be consistent with published experimental results. The qualitative behaviour of the HSR is expressed through a truth table. Through this novel approach, the authors have tried to develop a level of understanding of the interactions of the parts of the HSR system and of this system as a whole.

[1]  H. McAdams,et al.  Circuit simulation of genetic networks. , 1995, Science.

[2]  R. Morimoto,et al.  Pharmacological modulation of heat shock factor 1 by antiinflammatory drugs results in protection against stress-induced cellular damage. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Gregory D. Peterson,et al.  Engineering in the biological substrate: information processing in genetic circuits , 2004, Proceedings of the IEEE.

[4]  L. Glass,et al.  Evolving complex dynamics in electronic models of genetic networks. , 2004, Chaos.

[5]  B. Bukau,et al.  Protein Turnover: A CHIP Programmed for Proteolysis , 2002, Current Biology.

[6]  A. De Maio,et al.  Heat shock protein 70 binds its own messenger ribonucleic acid as part of a gene expression self-limiting mechanism , 2006, Cell stress & chaperones.

[7]  M Sugita,et al.  Functional analysis of chemical systems in vivo using a logical circuit equivalent. 3. Analysis using a digital circuit combined with an analogue computer. , 1963, Journal of theoretical biology.

[8]  M. Thattai,et al.  Attenuation of noise in ultrasensitive signaling cascades. , 2002, Biophysical journal.

[9]  Holly McDonough,et al.  CHIP: a link between the chaperone and proteasome systems , 2003, Cell stress & chaperones.

[10]  Bernd Bukau,et al.  The Hsp70 and Hsp60 Chaperone Machines , 1998, Cell.

[11]  John J. Tyson,et al.  The Dynamics of Feedback Control Circuits in Biochemical Pathways , 1978 .

[12]  M. Elowitz,et al.  A synthetic oscillatory network of transcriptional regulators , 2000, Nature.

[13]  J. Collins,et al.  Gene regulation: Neutralizing noise in gene networks , 2000, Nature.

[14]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[15]  R. Morimoto,et al.  Antiproliferative prostaglandins activate heat shock transcription factor. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[16]  R. Morimoto,et al.  Rapid and reversible relocalization of heat shock factor 1 within seconds to nuclear stress granules. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Mads Kaern,et al.  The engineering of gene regulatory networks. , 2003, Annual review of biomedical engineering.

[18]  B. Séraphin,et al.  Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion , 2001, The EMBO journal.

[19]  M Sugita,et al.  Functional analysis of chemical systems in vivo using a logical circuit equivalent. II. The idea of a molecular automation. , 1963, Journal of theoretical biology.

[20]  U. Srinivas,et al.  Role of heat shock transcription factors in stress response and during development , 1996, Journal of Biosciences.

[21]  R. Thomas,et al.  Boolean formalization of genetic control circuits. , 1973, Journal of theoretical biology.

[22]  E. Davidson,et al.  Modeling transcriptional regulatory networks. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[23]  Michael A. Savageau,et al.  Design principles for elementary gene circuits: Elements, methods, and examples. , 2001, Chaos.

[24]  D. A. Baxter,et al.  Modeling Circadian Oscillations with Interlocking Positive and Negative Feedback Loops , 2001, The Journal of Neuroscience.

[25]  Theodore R Rieger,et al.  Mathematical modeling of the eukaryotic heat-shock response: dynamics of the hsp70 promoter. , 2005, Biophysical journal.

[26]  John C. Doyle,et al.  Surviving heat shock: control strategies for robustness and performance. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  R. Morimoto,et al.  Attenuation of the heat shock response in HeLa cells is mediated by the release of bound heat shock transcription factor and is modulated by changes in growth and in heat shock temperatures. , 1991, Genes & development.

[28]  Ron Weiss,et al.  Cellular computation and communications using engineered genetic regulatory networks , 2001, Cellular Computing.

[29]  M. Horowitz,et al.  Heat acclimation increases the basal HSP72 level and alters its production dynamics during heat stress. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

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

[31]  A. De Maio,et al.  Thermotolerant Cells Show an Attenuated Expression of Hsp70 after Heat Shock* , 1999, The Journal of Biological Chemistry.

[32]  Jeff Hasty,et al.  Engineered gene circuits , 2002, Nature.

[33]  Jason C. Young,et al.  More than folding: localized functions of cytosolic chaperones. , 2003, Trends in biochemical sciences.

[34]  N. Gusev,et al.  Structure and Properties of Small Heat Shock Proteins (sHsp) and Their Interaction with Cytoskeleton Proteins , 2002, Biochemistry (Moscow).

[35]  Sang‐Gun Ahn,et al.  Heat-shock cognate 70 is required for the activation of heat-shock factor 1 in mammalian cells. , 2005, The Biochemical journal.

[36]  J. Kiang,et al.  Overexpression of HSP‐70 inhibits the phosphorylation of HSF1 by activating protein phosphatase and inhibiting protein kinase C activity , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  R Thomas,et al.  Dynamical behaviour of biological regulatory networks--I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state. , 1995, Bulletin of mathematical biology.

[38]  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 .

[39]  J. Monod,et al.  Genetic regulatory mechanisms in the synthesis of proteins. , 1961, Journal of molecular biology.