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Computational Modeling of the Eukaryotic Heat Shock Response

Computational modeling of the eukaryotic heat shock response

Academy of Finland, 2008-2010.

In cooperation with the Software Construction laboratory of TUCS (Academy Professor Ralph Back) and Turku Centre for Biotechnology (Academy Professor Lea Sistonen and Professor John Eriksson)

Cells exposed to elevated temperature or other stress stimuli respond by increased expression of heat shock proteins (HSPs). The heat shock response and the proteins involved have been highly conserved throughout evolution from Escherichia coli to human. In addition to heat, a wide variety of biological (infection, inflammation), physical (radiation, hypoxia) and chemical (alcohols, metals) stressors can induce the response. This is why the heat shock response is also called “stress response” and the heat shock proteins, in consequence, “stress proteins”.

The major HSPs are molecular chaperones with an essential role in directing protein folding and assembly of polypeptides within the cell. Under increased temperatures, the proportion of misfolded proteins (MFPs) suddenly increases and the cell reacts by synthesizing HSPs to assist those proteins in refolding. The stress response is controlled primarily at the transcription level (DNA is transcribed into RNA) by a heat shock factor (HSF). In unstressed cells, HSF is present in the cytoplasm and the nucleus in a monomeric form that has no DNA binding activity through its interactions with HSPs. In response to stress, the monomeric HSFs combine into trimers and accumulate within the nucleus. The response is very rapid, starting within minutes of the temperature rise. In the nucleus, the trimers bind to the heat shock elements (HSE), that is, specific DNA sequences in the heat shock gene promoters. When attached to DNA, HSF becomes phosphorylated. Phosphorylation is a process in which the chemical structure of a protein may be slightly altered, yet possibly leading to major changes in its three-dimensional fold and its function. The transcriptional activation of the heat shock genes leads to elevated levels of HSPs and to the formation of HSF-HSP complexes. Finally, once the stress is discontinued, the trimeric forms of HSF dissociate from the DNA and are converted back into non-active monomers, resulting in resumption of normal synthetic activities. The stress-dependent conversion of HSF into its active form implies that HSF is negatively regulated. The HSPs themselves may regulate the heat shock gene expression via an autoregulatory loop. According to this hypothesis, the increased concentrations of misfolded proteins formed during stress bind specific HSPs, resulting in the activation of HSF.

 

The sequence of events described above would generate accumulation of large amounts of HSPs, if the stress does not cease for a longer time. This effect would be detrimental to the cell, since HSPs are expensive in terms of energy consumption. Therefore, in such cases, the cell slows the HSP-synthesis as follows: HSPs (e.g., Hsp70, HSBP1) bind to HSFs, thus effectively inactivating the HSFs and making them unable to start the production of more HSPs. A model of the heat shock response can be seen in the figure below.

The Heat Shock Response Model

 

Figure1: The Heat Shock Response Model[1].

Physical or chemical stress induces production of unfolded or misfolded proteins. Heat shock factor (HSF) monomers in the cytoplasm form trimers, are phosphorylated, and translocate into the nucleus. HSF trimers bind to heat shock protein gene promoter regions (HSE), leading to induction of HSP gene transcription. Hsp70 gene transcription is down-regulated by interaction of Hsp70 or HSBP1 with the HSF trimers.

 

Links:

 

Bibliography:

  1. A. Graham Pockley. “Heat shock proteins as regulators of the immune response”. The Lancet. Published online April 29, 2003. http://image.thelancet.com/extras/02art9148web.pdf

Bionetgen Implementation of the Heat Shock Response

Bionetgen Implementation of the Heat Shock Response Bogdan Iancu has implemented the Bionetgen source code of the Heat Shock Response. It can be downloaded as a zip-file from here .

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Event-B Model for the Heat Shock Response

Event-B model for the Heat Shock Response Usman Sanwal, Luigia Petre and Ion Petre have built the Event-B model for the heat shock response The Rodin model can be downloaded here and their pdf printouts can be downloaded here.

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Heat Shock Response Simulator

Heat Shock Simulator Kristian Nylund has developed Heat Shock Simulator. It can be either downloaded as zip-file or started as java-applet in client’s browser window. ZIP file one can get here and the applet can be started from here

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Petri Net Implementation of the Heat Shock Response

Petri Net Implementation of the Heat Shock Response Diana-Elena Gratie has built Petri net models of the heat shock response. They can be downloaded as a zip-file from here . The latest standard and colored Petri net models are available here.

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PRISM Implementation of the Heat Shock Response

PRISM Implementation of the Heat Shock Response Sepinoud Azimi has implemented the PRISM source code of the Heat Shock Response. It can be downloaded as a zip-file from here .

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Seminar Series on Heat-Shock Response

Seminar Series on Heat-Shock Response We are running seminar series on computational aspects of eukaryotic heat-shock response. We will review the work already done in our group and elsewhere and we will try to identify the challenges posed by this research. All interested in are warmly welcome.   Schedule 5th of October Dr. Ion Petre …

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