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TRANSCRIPTIONAL REGULATION OF THE HEAT SHOCK RESPONSE

The stress-induced transcription of heat shock genes in vertebrates is mediated by the activities of a family of heat shock transcription factors (HSFs 1-4). We are characterizing the molecular properties of these HSFs, the role of positive and negative regulatory co-factors in sensing the stress signal and regulating their activities, the molecular events associated with activation of HSF DNA binding and acquisition of its transcriptional activity, and attenuation of HSF activity to its inert state.

At the cell biological level, HSF1 exhibits complex reversible subcellular localization from the inert monomer in the cytoplasmic and nuclear compartments to form distinctive chromosome 9q11-12-localized stress granules that contain the activated HSF1 trimers, a marker of heat shock activation in human cells. We are interested to understand the role of sub-nuclear compartmentalization of activated HSF1 and have proposed a role for HSF1 stress granules as a means to locally concentrate HSF1 to ensure that heat shock gene transcription is coordinately regulated.

We are interested in the temporal occupancy of the human Hsp70 promoter at the level of chromatin structure and promoter organization in response to stress, cell growth, oncogenes, and development, and the interplay between HSFs and these basal factors in the regulation of human heat shock gene transcription.

Using genome-wide strategies, we are employing C. elegans to understand how a complex multicellular metazoan senses and responds to stress using a combination of genetic and biochemical approaches. We are interested in questions on the regulation of heat shock gene expression during development and aging in response to different stress signals. Which genes are activated, in which tissues, at what times of development, and how are they regulated? These questions are being addressed using genomic approaches, bioinformatic analyses, and genetic approaches to identify new regulators and modulators of the heat shock response.

To understand the heat shock response at yet another level, we have developed (in collaboration with Prof. Vassily Hatzimanikatis in Chemical Engineering) a series of mathematical predictions for the regulation of the human heat shock response. This has allowed us to predict key points in the regulation of the heat shock response that are likely nodes of modulation that may become defective in certain tissues during development or associated with various pathologies.

References

  1. Westerheide, S.D., J. Anckar, S.M. Stevens, Jr., L. Sistonen, and R.I. Morimoto. Stress-Inducible Regulation of Heat Shock Factor 1 by the Deacetylase SIRT1. Science 20: 1063-1066 (2009).
  2. Prahlad, V., T. Cornelius and R.I. Morimoto, . Regulation of the Cellular Heat Shock Response in Caenorhabditis elegans by Thermosensory Neurons. Science 320: 811-814 (2008).
  3. Westerheide, S., T. Kawahara, K. Orton, and R.I. Morimoto, Triptolide, an Inhibitor of the Human Heat Shock Response that Enhances Stress-Induced Cell Death. J. Biol. Chem. 281: 9616-9622 (2006).
  4. Westerheide, S., and R.I. Morimoto. Heat Shock Response Modulators as Therapeutic Tools for Diseases of Protein Conformation. J. Biol. Chem. 380: 33097-33100 (2005).
  5. Rieger, T., R.I. Morimoto, and V. Hatzimanikatis. Mathematical Modeling of the Eukaryotic Heat Shock Response: Dynamics of the Hsp70 Promoter. Biophysical Journal 88: 1646-1658 (2005).
  6. Westerheide, S., J. Bosman, B. Mbadugha, T. Kawahara, G. Matsumoto, W. Gu, S. Kim, J. Devlin, R. Silverman, and R.I. Morimoto. Celastrols as Inducers of the Heat Shock Response and Cytoprotection J. Biol. Chem. 279: 56053-60 (2004).
  7. Morley, J.F. and Morimoto, R. Regulation of Longevity in Caenorhabditis elegans by Heat Shock Factor and Molecular Chaperones. Mol Biol Cell. Feb;15:657-64 (2004).
  8. Jolly, C., L. Konecny, D.L. Grady, Y.A. Kutskova, J.J. Cotto, R.I. Morimoto, and C. Vourch. In vivo Binding of Active HSF1 to Human Chromosome 9 Heterochromatin During Stress. J. Cell Biology 156: 775-781 (2002).
  9. Morimoto, R.I. Dynamic Remodeling of Transcription Complexes by Molecular Chaperones. Cell 110: 281-284 (2002)
  10. Mathew A, Mathur, SK, Jolly, C, Fox, SG, Kim, S and Morimoto RI. Stress-specific activation and repression of heat shock factors 1 and 2. Mol Cell Biol. 21: 7163-71 (2001).
  11. Ahn, S.-G.., P. Liu, K. Klyachko, R.I. Morimoto, and D. Thiele. The Loop Domain of Heat Shock Transcription Factor 1 Dictates DNA Binding Specificity and Responses to Heat Stress. Genes and Development 15: 2134-2145, 2001.
  12. Tai LJ, McFall SM, Huang K, Demeler B, Fox SG, Brubaker K, Radhakrishnan I, Morimoto RI. Structure-function analysis of the heat shock factor binding protein reveals a protein composed solely of a highly conserved and dynamic coiled-coil trimerization domain. J Biol Chem. (2001)
  13. Holmberg CI, Hietakangas V, Mikhailov A, Rantanen JO, Kallio M, Meinander A, Hellman J, Morrice N, MacKintosh C, Morimoto RI, Eriksson JE, Sistonen L. Phosphorylation of serine 230 promotes inducible transcriptional activity of heat shock factor 1. EMBO J 20: 3800-10 (2001)
  14. Jolly C. Usson Y. Morimoto RI. Rapid and reversible relocalization of heat shock factor 1 within seconds to nuclear stress granules. Proc National Academy of Science USA. 8;96(12):6769-74, 1999
  15. Tanabe M, Kawazoe Y, Takeda S, Morimoto RI, Nagata K, Nakai A Disruption of the HSF3 gene results in the severe reduction of heat shock gene expression and loss of thermotolerance. EMBO J 1998 Mar 16;17(6):1750-8
  16. Shi Y, Mosser DD, Morimoto RI Molecular chaperones as HSF1-specific transcriptional repressors. Genes Dev 1998 Mar 1;12(5):654-66
  17. Satyal SH, Chen D, Fox SG, Kramer JM, Morimoto RI Negative regulation of the heat shock transcriptional response by HSBP1. Genes Dev 1998 Jul 1;12(13):1962-7
  18. Mathew A, Mathur SK, Morimoto RI Heat shock response and protein degradation: regulation of HSF2 by the ubiquitin- proteasome pathway Mol Cell Biol:18(9):5091-8, 1998.
  19. Morimoto, RI. Regulation of the heat shock transcriptional response: Cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. (Review) Genes & Development, 12:3788-3796, 1998
  20. Kline MP. Morimoto RI . Repression of the heat shock factor 1 transcriptional activation domain is modulated by constitutive phosphorylation. Molecular & Cellular Biology. 17(4):2107-15, 1997
  21. Kanei-Ishii C. Tanikawa J. Nakai A. Morimoto RI. Ishii S . Activation of heat shock transcription factor 3 by c-Myb in the absence of cellular stress. Science. 277(5323):246-8, 1997
  22. Cotto J. Fox S. Morimoto R . HSF1 granules: a novel stress-induced nuclear compartment of human cells. Journal of Cell Science. 110 ( Pt 23):2925-34, 1997
  23. Jolly C. Morimoto R. Robert-Nicoud M. Vourc'h C . HSF1 transcription factor concentrates in nuclear foci during heat shock: relationship with transcription sites. Journal of Cell Science. 110 ( Pt 23):2935-41, 1997
  24. Cotto JJ. Kline M. Morimoto RI . Activation of heat shock factor 1 DNA binding precedes stress-induced serine phosphorylation. Evidence for a multistep pathway of regulation. Journal of Biological Chemistry. 271(7):3355-8, 1996
  25. Lee BS. Chen J. Angelidis C. Jurivich DA. Morimoto RI. Pharmacological modulation of heat shock factor 1 by antiinflammatory drugs results in protection against stress-induced cellular damage. Proceedings of the National Academy of Sciences of the United States of America. 92(16):7207-11, 1995
  26. Shi Y, Kroeger PE and Morimoto RI. The carboxyl-terminal transactivation domain of heat shock factor 1 is negatively regulated and stress responsive. Mol. Cell Biol., 15:4309-4318, 1995.
Transcriptional regulation of heat shock response
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All Chaperome Project
Misfolded and aggregation prone proteins in neu
C elegans as a model system for analysis of stress response and diseases of protein misfolding
Small molecule screen for the stress response
Systems Approach to Stress Biology