Heat Shock Response in CHO Mammalian Cells Is Controlled by a Nonlinear Stochastic Process

In many biological systems, the interactions that describe the coupling between different units in a genetic network are nonlinear and stochastic. We study the interplay between stochasticity and nonlinearity using the responses of Chinese hamster ovary (CHO) mammalian cells to different temperature shocks. The experimental data show that the mean value response of a cell population can be described by a mathematical expression (empirical law) which is valid for a large range of heat shock conditions. A nonlinear stochastic theoretical model was developed that explains the empirical law for the mean response. Moreover, the theoretical model predicts a specific biological probability distribution of responses for a cell population. The prediction was experimentally confirmed by measurements at the single-cell level. The computational approach can be used to study other nonlinear stochastic biological phenomena.

[1]  Ertugrul M. Ozbudak,et al.  Predicting stochastic gene expression dynamics in single cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Jonathan Weissman,et al.  Molecular Chaperones and Protein Quality Control , 2006, Cell.

[3]  C. Moonen,et al.  Spatial and temporal control of expression of therapeutic genes using heat shock protein promoters. , 2005, Methods.

[4]  Wing H Wong,et al.  Is the future biology Shakespearean or Newtonian? , 2006, Molecular bioSystems.

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

[6]  Nir Friedman,et al.  Linking stochastic dynamics to population distribution: an analytical framework of gene expression. , 2006, Physical review letters.

[7]  Christopher J. Nichols,et al.  Hsp70 dynamics in vivo: effect of heat shock and protein aggregation , 2004, Journal of Cell Science.

[8]  R. Morimoto,et al.  Repression of the heat shock factor 1 transcriptional activation domain is modulated by constitutive phosphorylation , 1997, Molecular and cellular biology.

[9]  M. Borrelli,et al.  Heat-activated transgene expression from adenovirus vectors infected into human prostate cancer cells. , 2001, Cancer research.

[10]  D. Endy.  Foundations for engineering biology , 2005, Nature.

[11]  W. H. Furry.  On Fluctuation Phenomena in the Passage of High Energy Electrons through Lead , 1937 .

[12]  C. Moonen,et al.  Control of transgene expression using local hyperthermia in combination with a heat‐sensitive promoter , 2000, The journal of gene medicine.

[13]  Lea Sistonen,et al.  Multisite phosphorylation provides sophisticated regulation of transcription factors. , 2002, Trends in biochemical sciences.

[14]  L. Sistonen,et al.  Roles of the heat shock transcription factors in regulation of the heat shock response and beyond , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

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

[16]  D. Sherrington.  Stochastic Processes in Physics and Chemistry , 1983 .

[17]  T. Michiue,et al.  Temporal and spatial manipulation of gene expression in Xenopus embryos by injection of heat shock promoter‐containing plasmids , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[18]  A. Barabasi,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[19]  T. Ideker,et al.  A new approach to decoding life: systems biology. , 2001, Annual review of genomics and human genetics.

[20]  S Achimescu,et al.  Signal propagation in nonlinear stochastic gene regulatory networks. , 2005, Systems biology.

[21]  T. Foster,et al.  Activation of Heat Shock Protein 70 Promoter with meso‐Tetrahydroxyphenyl Chlorin Photodynamic Therapy Reported by Green Fluorescent Protein In Vitro and In Vivo ¶ , 2003, Photochemistry and photobiology.

[22]  W. Ebeling.  Stochastic Processes in Physics and Chemistry , 1995 .

[23]  Farren J. Isaacs,et al.  RNA synthetic biology , 2006, Nature Biotechnology.

[24]  M. Ehrenberg,et al.  Random signal fluctuations can reduce random fluctuations in regulated components of chemical regulatory networks. , 2000, Physical review letters.

[25]  R. Kingston,et al.  Heat-inducible human factor that binds to a human hsp70 promoter , 1987, Molecular and cellular biology.

[26]  Ovidiu Lipan,et al.  The use of oscillatory signals in the study of genetic networks. , 2005, Proceedings of the National Academy of Sciences of the United States of America.