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Controlling gene expression in response to stress

Nature Reviews Genetics volume 12, pages 833–845 (2011)Cite this article

Subjects

Key Points

  • Exposure of cells to suboptimal growth conditions or to any environment that reduces cell viability or fitness can be considered a stress.

  • Adaptive responses to stress depend on the organism and are comprised of both generic responses shared by many stresses and specific responses dedicated to particular stresses.

  • Eukaryotic cells have evolved sophisticated sensing mechanisms and signal transduction systems that can produce accurate dynamic outcomes in response to stresses.

  • Adaptation to stress involves an extensive reorganization of the gene expression programme.

  • Control of gene expression following exposure to stress is tightly regulated and reversible. This control is achieved by different molecular mechanisms that are highly dependent on the particular stress and organism.

  • The pattern of gene expression that is observed in response to stress is achieved by fine regulation of multiple steps of the mRNA biogenesis and mRNA fate.

  • Nucleosome remodelling is important in stress-induced gene expression and might be important in providing transcriptional activators and general transcription machinery with full access to stress-responsive genes.

  • RNA polymerase II pausing is a mechanism that enables rapid gene induction, and it is used in several organisms to coordinate gene expression.

  • Signalling kinases are an integral part of transcription platforms.

Abstract

Acute stress puts cells at risk, and rapid adaptation is crucial for maximizing cell survival. Cellular adaptation mechanisms include modification of certain aspects of cell physiology, such as the induction of efficient changes in the gene expression programmes by intracellular signalling networks. Recent studies using genome-wide approaches as well as single-cell transcription measurements, in combination with classical genetics, have shown that rapid and specific activation of gene expression can be accomplished by several different strategies. This article discusses how organisms can achieve generic and specific responses to different stresses by regulating gene expression at multiple stages of mRNA biogenesis from chromatin structure to transcription, mRNA stability and translation.

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Figure 1: The HOG signalling pathway.
Figure 2: Mammalian stress signalling by p38 MAPKs.
Figure 3: Control of gene expression by the HSF transcription factor in Drosophila melanogaster.

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References

  1. Nadeau, S. I. & Landry, J. Mechanisms of activation and regulation of the heat shock-sensitive signaling pathways. Adv. Exp. Med. Biol. 594, 100–113 (2007).

    Article  PubMed  Google Scholar 

  2. Richter, K., Haslbeck, M. & Buchner, J. The heat shock response: life on the verge of death. Mol. Cell 40, 253–266 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Riezman, H. Why do cells require heat shock proteins to survive heat stress? Cell Cycle 3, 61–63 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Chen, R. E. & Thorner, J. Function and regulation in MAPK signaling pathways: lessons learned from the yeast Saccharomyces cerevisiae. Biochim. Biophys. Acta 1773, 1311–1340 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gehart, H., Kumpf, S., Ittner, A. & Ricci, R. MAPK signalling in cellular metabolism: stress or wellness? EMBO Rep. 11, 834–840 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hohmann, S. Osmotic stress signaling and osmoadaptation in yeasts. Microbiol. Mol. Biol. Rev. 66, 300–372 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hohmann, S., Krantz, M. & Nordlander, B. Yeast osmoregulation. Methods Enzymol. 428, 29–45 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. O'Rourke, S. M., Herskowitz, I. & O'Shea, E. K. Yeast go the whole HOG for the hyperosmotic response. Trends Genet. 18, 405–412 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Westfall, P. J., Ballon, D. R. & Thorner, J. When the stress of your environment makes you go HOG wild. Science 306, 1511–1512 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Akerfelt, M., Morimoto, R. I. & Sistonen, L. Heat shock factors: integrators of cell stress, development and lifespan. Nature Rev. Mol. Cell Biol. 11, 545–555 (2010).

    Article  CAS  Google Scholar 

  11. Guertin, M. J., Petesch, S. J., Zobeck, K. L., Min, I. M. & Lis, J. T. Drosophila heat shock system as a general model to investigate transcriptional regulation. Cold Spring Harb. Symp. Quant. Biol. 75, 1–9 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Sakurai, H. & Enoki, Y. Novel aspects of heat shock factors: DNA recognition, chromatin modulation and gene expression. FEBS J. 277, 4140–4149 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Martinez-Montanes, F., Pascual-Ahuir, A. & Proft, M. Toward a genomic view of the gene expression program regulated by osmostress in yeast. OMICS 14, 619–627 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. de Nadal, E. & Posas, F. Multilayered control of gene expression by stress-activated protein kinases. EMBO J. 29, 4–13 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Weake, V. M. & Workman, J. L. Inducible gene expression: diverse regulatory mechanisms. Nature Rev. Genet. 11, 426–437 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Causton, H. C. et al. Remodeling of yeast genome expression in response to environmental changes. Mol. Biol. Cell 12, 323–337 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gasch, A. P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000). This was one of the initial studies that described global genomic expression patterns in response to diverse cellular stimuli in yeast. Using DNA microarrays, the authors describe a transcriptional response that is common to almost all environmental changes and another that is specialized for specific conditions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sorensen, J. G., Nielsen, M. M., Kruhoffer, M., Justesen, J. & Loeschcke, V. Full genome gene expression analysis of the heat stress response in Drosophila melanogaster. Cell Stress. Chaperones 10, 312–328 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yale, J. & Bohnert, H. J. Transcript expression in Saccharomyces cerevisiae at high salinity. J. Biol. Chem. 276, 15996–16007 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Horie, T., Tatebayashi, K., Yamada, R. & Saito, H. Phosphorylated Ssk1 prevents unphosphorylated Ssk1 from activating the Ssk2 mitogen-activated protein kinase kinase kinase in the yeast high-osmolarity glycerol osmoregulatory pathway. Mol. Cell Biol. 28, 5172–5183 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kaserer, A. O., Andi, B., Cook, P. F. & West, A. H. Effects of osmolytes on the SLN1-YPD1-SSK1 phosphorelay system from Saccharomyces cerevisiae. Biochemistry 48, 8044–8050 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Egger, L. A., Park, H. & Inouye, M. Signal transduction via the histidyl-aspartyl phosphorelay. Genes Cells 2, 167–184 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Tatebayashi, K. et al. Transmembrane mucins Hkr1 and Msb2 are putative osmosensors in the SHO1 branch of yeast HOG pathway. EMBO J. 26, 3521–3533 (2007). The authors of this paper showed that the yeast mucin-like transmembrane proteins Hkr1 and Msb2 are potential osmosensors that activates the Sho1-branch of the HOG SAPK pathway in response to osmostress. Because mucins activate a number of signalling cascades in mammals, they could be important for sensing osmotic imbalances in higher eukaryotes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yamamoto, K., Tatebayashi, K., Tanaka, K. & Saito, H. Dynamic control of yeast MAP kinase network by induced association and dissociation between the Ste50 scaffold and the Opy2 membrane anchor. Mol. Cell 40, 87–98 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. de Nadal, E., Real, F. X. & Posas, F. Mucins, osmosensors in eukaryotic cells? Trends Cell Biol. 17, 571–574 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Franzmann, T. M., Menhorn, P., Walter, S. & Buchner, J. Activation of the chaperone Hsp26 is controlled by the rearrangement of its thermosensor domain. Mol. Cell 29, 207–216 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Klinkert, B. & Narberhaus, F. Microbial thermosensors. Cell. Mol. Life Sci. 66, 2661–2676 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Hamada, F. N. et al. An internal thermal sensor controlling temperature preference in Drosophila. Nature 454, 217–220 (2008). This work identified a thermal sensing pathway in D. melanogaster that is tuned to avoid non-preferred temperatures. The ion channel dTrpA1 functions as a molecular sensor of temperature and activates a small set of anterior cell neurons, the function of which is crucial for selection of preferred temperatures.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. McClung, C. R. & Davis, S. J. Ambient thermometers in plants: from physiological outputs towards mechanisms of thermal sensing. Curr. Biol. 20, R1086–R1092 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Kyriakis, J. M. & Avruch, J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81, 807–869 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Wagner, E. F. & Nebreda, A. R. Signal integration by JNK and p38 MAPK pathways in cancer development. Nature Rev. Cancer 9, 537–549 (2009).

    Article  CAS  Google Scholar 

  32. Cuadrado, A. & Nebreda, A. R. Mechanisms and functions of p38 MAPK signalling. Biochem. J. 429, 403–417 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Cuevas, B. D., Abell, A. N. & Johnson, G. L. Role of mitogen-activated protein kinase kinase kinases in signal integration. Oncogene 26, 3159–3171 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Krantz, M. et al. Robustness and fragility in the yeast high osmolarity glycerol (HOG) signal-transduction pathway. Mol. Syst. Biol. 5, 281 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Tomida, T., Takekawa, M., O'Grady, P. & Saito, H. Stimulus-specific distinctions in spatial and temporal dynamics of stress-activated protein kinase kinase kinases revealed by a fluorescence resonance energy transfer biosensor. Mol. Cell Biol. 29, 6117–6127 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Luyten, K. et al. Fps1, a yeast member of the MIP family of channel proteins, is a facilitator for glycerol uptake and efflux and is inactive under osmotic stress. EMBO J. 14, 1360–1371 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Proft, M. & Struhl, K. MAP kinase-mediated stress relief that precedes and regulates the timing of transcriptional induction. Cell 118, 351–361 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Berry, D. B. & Gasch, A. P. Stress-activated genomic expression changes serve a preparative role for impending stress in yeast. Mol. Biol. Cell 19, 4580–4587 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lopez-Maury, L., Marguerat, S. & Bahler, J. Tuning gene expression to changing environments: from rapid responses to evolutionary adaptation. Nature Rev. Genet. 9, 583–593 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Westfall, P. J., Patterson, J. C., Chen, R. E. & Thorner, J. Stress resistance and signal fidelity independent of nuclear MAPK function. Proc. Natl Acad. Sci. USA 105, 12212–12217 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Capaldi, A. P. et al. Structure and function of a transcriptional network activated by the MAPK Hog1. Nature Genet. 40, 1300–1306 (2008). This paper provided a quantitive model of the yeast HOG SAPK signalling pathway in response to osmostress. Using gene expression and ChIP followed by microarray (ChIP–chip) analyses, the authors found that Hog1 activity is spread out to multiple transcription factors, and this permits a specific response that depends on the association of the promoters and transcription factors, creating a context-dependent response.

    Article  CAS  PubMed  Google Scholar 

  42. Ni, L. et al. Dynamic and complex transcription factor binding during an inducible response in yeast. Genes Dev. 23, 1351–1363 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miller, C. et al. Dynamic transcriptome analysis measures rates of mRNA synthesis and decay in yeast. Mol. Syst. Biol. 7, 458 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Boehm, A. K., Saunders, A., Werner, J. & Lis, J. T. Transcription factor and polymerase recruitment, modification, and movement on dhsp70 in vivo in the minutes following heat shock. Mol. Cell Biol. 23, 7628–7637 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yaakov, G., Bell, M., Hohmann, S. & Engelberg, D. Combination of two activating mutations in one HOG1 gene forms hyperactive enzymes that induce growth arrest. Mol. Cell Biol. 23, 4826–4840 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vendrell, A. et al. Sir2 histone deacetylase prevents programmed cell death caused by sustained activation of the Hog1 stress-activated protein kinase. EMBO Rep. 12, 1062–1068 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dolado, I. & Nebreda, A. R. AKT and oxidative stress team up to kill cancer cells. Cancer Cell 14, 427–429 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Nollen, E. A. & Morimoto, R. I. Chaperoning signaling pathways: molecular chaperones as stress-sensing 'heat shock' proteins. J. Cell Sci. 115, 2809–2816 (2002).

    CAS  PubMed  Google Scholar 

  49. Klipp, E., Nordlander, B., Kruger, R., Gennemark, P. & Hohmann, S. Integrative model of the response of yeast to osmotic shock. Nature Biotech. 23, 975–982 (2005).

    Article  CAS  Google Scholar 

  50. Hohmann, S. Control of high osmolarity signalling in the yeast Saccharomyces cerevisiae. FEBS Lett. 583, 4025–4029 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Brandman, O. & Meyer, T. Feedback loops shape cellular signals in space and time. Science 322, 390–395 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Molina, M., Cid, V. J. & Martin, H. Fine regulation of Saccharomyces cerevisiae MAPK pathways by post-translational modifications. Yeast 27, 503–511 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Mettetal, J. T., Muzzey, D., Gomez-Uribe, C. & van Oudenaarden A. The frequency dependence of osmo-adaptation in Saccharomyces cerevisiae. Science 319, 482–484 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Muzzey, D., Gomez-Uribe, C. A., Mettetal, J. T. & van Oudenaarden A. A systems-level analysis of perfect adaptation in yeast osmoregulation. Cell 138, 160–171 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Macia, J. et al. Dynamic signaling in the Hog1 MAPK pathway relies on high basal signal transduction. Sci. Signal. 2, ra13 (2009).

    Article  PubMed  Google Scholar 

  56. Gasch, A. P. Comparative genomics of the environmental stress response in ascomycete fungi. Yeast 24, 961–976 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Alejandro-Osorio, A. L. et al. The histone deacetylase Rpd3p is required for transient changes in genomic expression in response to stress. Genome Biol. 10, R57 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Murray, J. I. et al. Diverse and specific gene expression responses to stresses in cultured human cells. Mol. Biol. Cell 15, 2361–2374 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ferreiro, I. et al. Whole genome analysis of p38 SAPK-mediated gene expression upon stress. BMC. Genomics 11, 144 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Giaever, G. et al. Functional profiling of the Saccharomyces cerevisiae genome. Nature 418, 387–391 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Zapater, M., Sohrmann, M., Peter, M., Posas, F. & de Nadal E. Selective requirement for SAGA in Hog1-mediated gene expression depending on the severity of the external osmostress conditions. Mol. Cell. Biol. 27, 3900–3910 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Auesukaree, C. et al. Genome-wide identification of genes involved in tolerance to various environmental stresses in Saccharomyces cerevisiae. J. Appl. Genet. 50, 301–310 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Ruiz-Roig, C., Vieitez, C., Posas, F. & de Nadal, E. The Rpd3L HDAC complex is essential for the heat stress response in yeast. Mol. Microbiol. 76, 1049–1062 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Mas, G. et al. Recruitment of a chromatin remodelling complex by the Hog1 MAP kinase to stress genes. EMBO J. 28, 326–336 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Proft, M. & Struhl, K. Hog1 kinase converts the Sko1–Cyc8–Tup1 repressor complex into an activator that recruits SAGA and SWI/SNF in response to osmotic stress. Mol. Cell 9, 1307–1317 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Shivaswamy, S. et al. Dynamic remodeling of individual nucleosomes across a eukaryotic genome in response to transcriptional perturbation. PLoS. Biol. 6, e65 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Erkina, T. Y., Zou, Y., Freeling, S., Vorobyev, V. I. & Erkine, A. M. Functional interplay between chromatin remodeling complexes RSC, SWI/SNF and ISWI in regulation of yeast heat shock genes. Nucleic Acids Res. 38, 1441–1449 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Venters, B. J. et al. A comprehensive genomic binding map of gene and chromatin regulatory proteins in Saccharomyces. Mol. Cell 41, 480–492 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Klopf, E. et al. Cooperation between the INO80 complex and histone chaperones determines adaptation of stress gene transcription in the yeast Saccharomyces cerevisiae. Mol. Cell. Biol. 29, 4994–5007 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mavrich, T. N. et al. Nucleosome organization in the Drosophila genome. Nature 453, 358–362 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Petesch, S. J. & Lis, J. T. Rapid, transcription-independent loss of nucleosomes over a large chromatin domain at Hsp70 loci. Cell 134, 74–84 (2008). This study showed that heat shock induces a widespread loss of canonical nucleosome signals within seconds across the Hsp70 locus in D. melanogaster cells. Surprisingly, this nucleosome disruption occurred prior to the passage of the polymerase and is independent of transcription, indicating that nucleosome loss by itself is not sufficient to activate transcription.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Winegarden, N. A., Wong, K. S., Sopta, M. & Westwood, J. T. Sodium salicylate decreases intracellular ATP, induces both heat shock factor binding and chromosomal puffing, but does not induce hsp 70 gene transcription in Drosophila. J. Biol. Chem. 271, 26971–26980 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Pelet, S. et al. Transient activation of the HOG MAPK pathway regulates bimodal gene expression. Science 332, 732–735 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. de Nadal, E. et al. The MAPK Hog1 recruits Rpd3 histone deacetylase to activate osmoresponsive genes. Nature 427, 370–374 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Guertin, M. J. & Lis, J. T. Chromatin landscape dictates HSF binding to target DNA elements. PLoS. Genet. 6, (2010).

  76. Huang, H. et al. HistoneHits: a database for histone mutations and their phenotypes. Genome Res. 19, 674–681 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zanton, S. J. & Pugh, B. F. Full and partial genome-wide assembly and disassembly of the yeast transcription machinery in response to heat shock. Genes Dev. 20, 2250–2265 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zanton, S. J. & Pugh, B. F. Changes in genomewide occupancy of core transcriptional regulators during heat stress. Proc. Natl Acad. Sci. USA 101, 16843–16848 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Alepuz, P. M., de Nadal, E., Zapater, M., Ammerer, G. & Posas, F. Osmostress-induced transcription by Hot1 depends on a Hog1-mediated recruitment of the RNA Pol II. EMBO J. 22, 2433–2442 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Proft, M. et al. Regulation of the Sko1 transcriptional repressor by the Hog1 MAP kinase in response to osmotic stress. EMBO J. 20, 1123–1133 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. de Nadal, E., Casadome, L. & Posas, F. Targeting the MEF2-like transcription factor Smp1 by the stress-activated Hog1 mitogen-activated protein kinase. Mol. Cell. Biol. 23, 229–237 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Pokholok, D. K., Zeitlinger, J., Hannett, N. M., Reynolds, D. B. & Young, R. A. Activated signal transduction kinases frequently occupy target genes. Science 313, 533–536 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Kim, K. Y., Truman, A. W. & Levin, D. E. Yeast Mpk1 mitogen-activated protein kinase activates transcription through Swi4/Swi6 by a noncatalytic mechanism that requires upstream signal. Mol. Cell Biol. 28, 2579–2589 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Li, H., Tsang, C. K., Watkins, M., Bertram, P. G. & Zheng, X. F. Nutrient regulates Tor1 nuclear localization and association with rDNA promoter. Nature 442, 1058–1061 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Chow, C. W. & Davis, R. J. Proteins kinases: chromatin-associated enzymes? Cell 127, 887–890 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Edmunds, J. W. & Mahadevan, L. C. Cell signaling. Protein kinases seek close encounters with active genes. Science 313, 449–451 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Alepuz, P. M., Jovanovic, A., Reiser, V. & Ammerer, G. Stress-induced map kinase Hog1 is part of transcription activation complexes. Mol. Cell 7, 767–777 (2001). The authors showed that association of the Hog1 kinase to promoter regions mediates stress-responsive gene activation. This was a key finding that demonstrated the binding of signalling kinases to chromatin.

    Article  CAS  PubMed  Google Scholar 

  88. Proft, M. et al. The stress-activated Hog1 kinase is a selective transcriptional elongation factor for genes responding to osmotic stress. Mol. Cell 23, 241–250 (2006). This paper showed that the Hog1 SAPK associates with elongating polymerase and it is selectively recruited to coding regions of genes induced in response to osmostress. Moreover, Hog1 is essential for an increased density of active polymerase in the coding regions. These findings indicated a new and unexpectedly role of SAPK during transcriptional elongation.

    Article  CAS  PubMed  Google Scholar 

  89. Pascual-Ahuir, A., Struhl, K. & Proft, M. Genome-wide location analysis of the stress-activated MAP kinase Hog1 in yeast. Methods 40, 272–278 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Sole, C. et al. Control of Ubp3 ubiquitin protease activity by the Hog1 SAPK modulates transcription upon osmostress. EMBO J. 30, 3274–3284 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ferreiro, I. et al. The p38 SAPK is recruited to chromatin via its interaction with transcription factors. J. Biol. Chem. 285, 31819–31828 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Simone, C. et al. p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci. Nature Genet. 36, 738–743 (2004). The authors showed that activated p38 is recruited to chromatin of muscle-regulatory elements during skeletal myogenesis, and it targets the SWI/SNF chromatin-remodelling complex to myogenic loci. This is a key article that highlights the links between signalling kinases and chromatin in higher eukaryotes.

    Article  CAS  PubMed  Google Scholar 

  93. Serra, C. et al. Functional interdependence at the chromatin level between the MKK6/p38 and IGF1/PI3K/AKT pathways during muscle differentiation. Mol. Cell 28, 200–213 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Vicent, G. P. et al. Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3. Mol. Cell 24, 367–381 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Zhang, H. M. et al. Mitogen-induced recruitment of ERK and MSK to SRE promoter complexes by ternary complex factor Elk-1. Nucleic Acids Res. 36, 2594–2607 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nature Genet. 39, 1512–1516 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Muse, G. W. et al. RNA polymerase is poised for activation across the genome. Nature Genet. 39, 1507–1511 (2007). This work shows that polymerase stalling within the promoter-proximal region is a widespread phenomenon across the D. melanogaster genome that occurs at many developmentally and stimulus-regulated genes. This is a key finding because it pointed out stalled polymerases as a central phenomenon for transcription regulation.

    Article  CAS  PubMed  Google Scholar 

  98. Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lis, J. T. Imaging Drosophila gene activation and polymerase pausing in vivo. Nature 450, 198–202 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Core, L. J. & Lis, J. T. Transcription regulation through promoter-proximal pausing of RNA polymerase II. Science 319, 1791–1792 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Levine, M. Paused RNA polymerase II as a developmental checkpoint. Cell 145, 502–511 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rougvie, A. E. & Lis, J. T. The RNA polymerase II molecule at the 5′ end of the uninduced hsp70 gene of D. melanogaster is transcriptionally engaged. Cell 54, 795–804 (1988). This was one of the first studies to show the presence of paused polymerase that is associated with the promoter region prior to induction of transcription.

    Article  CAS  PubMed  Google Scholar 

  103. Zobeck, K. L., Buckley, M. S., Zipfel, W. R. & Lis, J. T. Recruitment timing and dynamics of transcription factors at the Hsp70 loci in living cells. Mol. Cell 40, 965–975 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zou, J., Guo, Y., Guettouche, T., Smith, D. F. & Voellmy, R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94, 471–480 (1998).

    Article  CAS  PubMed  Google Scholar 

  105. Fujimoto, M. & Nakai, A. The heat shock factor family and adaptation to proteotoxic stress. FEBS J. 277, 4112–4125 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Lis, J. T., Mason, P., Peng, J., Price, D. H. & Werner, J. P-TEFb kinase recruitment and function at heat shock loci. Genes Dev. 14, 792–803 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Price, D. H. Poised polymerases: on your mark.get set.go! Mol. Cell 30, 7–10 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Wu, C. H. et al. NELF and DSIF cause promoter proximal pausing on the hsp70 promoter in Drosophila. Genes Dev. 17, 1402–1414 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Fivaz, J., Bassi, M. C., Pinaud, S. & Mirkovitch, J. RNA polymerase II promoter-proximal pausing upregulates c-fos gene expression. Gene 255, 185–194 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Hitti, E. et al. Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Mol. Cell. Biol. 26, 2399–2407 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sandler, H. & Stoecklin, G. Control of mRNA decay by phosphorylation of tristetraprolin. Biochem. Soc. Trans. 36, 491–496 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Farooq, F., Balabanian, S., Liu, X., Holcik, M. & Mackenzie, A. p38 Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR. Hum. Mol. Genet. 18, 4035–4045 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Lafarga, V. et al. p38 Mitogen-activated protein kinase- and HuR-dependent stabilization of p21(Cip1) mRNA mediates the G1/S checkpoint. Mol. Cell. Biol. 29, 4341–4351 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Castells-Roca, L. et al. Heat shock response in yeast involves changes in both transcription rates and mRNA stabilities. PLoS ONE 6, e17272 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Molin, C., Jauhiainen, A., Warringer, J., Nerman, O. & Sunnerhagen, P. mRNA stability changes precede changes in steady-state mRNA amounts during hyperosmotic stress. RNA 15, 600–614 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Romero-Santacreu, L., Moreno, J., Perez-Ortin, J. E. & Alepuz, P. Specific and global regulation of mRNA stability during osmotic stress in Saccharomyces cerevisiae. RNA 15, 1110–1120 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Shalem, O. et al. Transient transcriptional responses to stress are generated by opposing effects of mRNA production and degradation. Mol. Syst. Biol. 4, 223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Spriggs, K. A., Bushell, M. & Willis, A. E. Translational regulation of gene expression during conditions of cell stress. Mol. Cell 40, 228–237 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Vries, R. G. et al. Heat shock increases the association of binding protein-1 with initiation factor 4E. J. Biol. Chem. 272, 32779–32784 (1997).

    Article  CAS  PubMed  Google Scholar 

  120. Wang, X. et al. The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways. J. Biol. Chem. 273, 9373–9377 (1998).

    Article  CAS  PubMed  Google Scholar 

  121. Coldwell, M. J. et al. The p36 isoform of BAG-1 is translated by internal ribosome entry following heat shock. Oncogene 20, 4095–4100 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Cuesta, R., Laroia, G. & Schneider, R. J. Chaperone hsp27 inhibits translation during heat shock by binding eIF4G and facilitating dissociation of cap-initiation complexes. Genes Dev. 14, 1460–1470 (2000). This study identifies chaperone HSP27 as a heat-shock-induced inhibitor of cellular protein synthesis by targeting the adaptor protein eIF4G. Hsp27 and eIF4G binding prevents assembly of the cap-initiation–eIF4F complex and restricts eIF4G in insoluble heat shock granules.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Ma, S., Bhattacharjee, R. B. & Bag, J. Expression of poly(A)-binding protein is upregulated during recovery from heat shock in HeLa cells. FEBS J. 276, 552–570 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Warringer, J., Hult, M., Regot, S., Posas, F. & Sunnerhagen, P. The HOG pathway dictates the short-term translational response after hyperosmotic shock. Mol. Biol. Cell 21, 3080–3092 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Uesono, Y. & Toh, E. Transient inhibition of translation initiation by osmotic stress. J. Biol. Chem. 277, 13848–13855 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Bilsland-Marchesan, E., Arino, J., Saito, H., Sunnerhagen, P. & Posas, F. Rck2 kinase is a substrate for the osmotic stress-activated mitogen-activated protein kinase Hog1. Mol. Cell. Biol. 20, 3887–3895 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Teige, M., Scheikl, E., Reiser, V., Ruis, H. & Ammerer, G. Rck2, a member of the calmodulin-protein kinase family, links protein synthesis to high osmolarity MAP kinase signaling in budding yeast. Proc. Natl Acad. Sci. USA 98, 5625–5630 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Albertyn, J., Hohmann, S., Thevelein, J. M. & Prior, B. A. GPD1, which encodes glycerol-3-phosphate dehydrogenase, is essential for growth under osmotic stress in Saccharomyces cerevisiae, and its expression is regulated by the high-osmolarity glycerol response pathway. Mol. Cell. Biol. 14, 4135–4144 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. de Nadal, E., Alepuz, P. M. & Posas, F. Dealing with osmostress through MAP kinase activation. EMBO Rep. 3, 735–740 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Clotet, J. & Posas, F. Control of cell cycle in response to osmostress: lessons from yeast. Methods Enzymol. 428, 63–76 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Posas, F., Takekawa, M. & Saito, H. Signal transduction by MAP kinase cascades in budding yeast. Curr. Opin. Microbiol. 1, 175–182 (1998).

    Article  CAS  PubMed  Google Scholar 

  132. Ferrigno, P., Posas, F., Koepp, D., Saito, H. & Silver, P. A. Regulated nucleo/cytoplasmic exchange of HOG1 MAPK requires the importin β homologs NMD5 and XPO1. EMBO J. 17, 5606–5614 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Reiser, V., Ruis, H. & Ammerer, G. Kinase activity-dependent nuclear export opposes stress-induced nuclear accumulation and retention of Hog1 mitogen-activated protein kinase in the budding yeast Saccharomyces cerevisiae. Mol. Biol. Cell 10, 1147–1161 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Saito, H. & Tatebayashi, K. Regulation of the osmoregulatory HOG MAPK cascade in yeast. J. Biochem. (Tokyo) 136, 267–272 (2004).

    Article  CAS  Google Scholar 

  135. Sheikh-Hamad, D. & Gustin, M. C. MAP kinases and the adaptive response to hypertonicity: functional preservation from yeast to mammals. Am. J. Physiol. Renal Physiol. 287, F1102-F1110 (2004).

    Article  CAS  Google Scholar 

  136. Yao, J., Ardehali, M. B., Fecko, C. J., Webb, W. W. & Lis, J. T. Intranuclear distribution and local dynamics of RNA polymerase II during transcription activation. Mol. Cell 28, 978–990 (2007). By two-photon microscopy in live polytene nuclei and by fluorescence in situ hybridization (FISH) in diploid nuclei, this study in D. melanogaster assessed the location, movement and transcriptional dynamics of highly transcribed heat shock genes.

    Article  CAS  PubMed  Google Scholar 

  137. Arthur, J. S. MSK activation and physiological roles. Front. Biosci. 13, 5866–5879 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Cuenda, A. & Rousseau, S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim. Biophys. Acta 1773, 1358–1375 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Roux, P. P. & Blenis, J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev. 68, 320–344 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Mahalingam, M. & Cooper, J. A. Phosphorylation of mammalian eIF4E by Mnk1 and Mnk2: tantalizing prospects for a role in translation. Prog. Mol. Subcell. Biol. 27, 132–142 (2001).

    CAS  PubMed  Google Scholar 

  141. Rampalli, S. et al. p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation. Nature Struct. Mol. Biol. 14, 1150–1156 (2007).

    Article  CAS  Google Scholar 

  142. Lee, C. et al. NELF and GAGA factor are linked to promoter-proximal pausing at many genes in Drosophila. Mol. Cell. Biol. 28, 3290–3300 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Tsukiyama, T., Becker, P. B. & Wu, C. ATP-dependent nucleosome disruption at a heat-shock promoter mediated by binding of GAGA transcription factor. Nature 367, 525–532 (1994).

    Article  CAS  PubMed  Google Scholar 

  144. Wang, Y. V., Tang, H. & Gilmour, D. S. Identification in vivo of different rate-limiting steps associated with transcriptional activators in the presence and absence of a GAGA element. Mol. Cell. Biol. 25, 3543–3552 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lee, H., Kraus, K. W., Wolfner, M. F. & Lis, J. T. DNA sequence requirements for generating paused polymerase at the start of hsp70. Genes Dev. 6, 284–295 (1992).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The laboratory of F.P. and E.d.N. is supported by grants from the Ministerio de Ciéncia y Innovación, the Consolider Ingenio 2010 programme and FP7 UNICELLSYS grant to F.P., E.d.N. and G.A. F.P. is also supported by the Fundación Marcelino Botín (FMB) and ICREA Acadèmia (Generalitat de Catalunya). We apologize to colleagues in the field for not citing all relevant papers owing to space constraints.

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Authors and Affiliations

  1. Cell Signaling Unit, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, E-08003, Spain

    Eulàlia de Nadal & Francesc Posas

  2. Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Vienna, A-1030, Austria

    Gustav Ammerer

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  1. Eulàlia de Nadal
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Correspondence to Francesc Posas.

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Glossary

Mucin

Mucins are a family of high-molecular-mass glycoproteins characterized by a high content of Ser and Thr residues that are organized as heavily glycosylated tandem repeats. Mucins are the main components of mucus, an adhesive and viscoelastic gel covering the surface of internal epithelia.

Thermosensory structures

Biomolecules that contain particular structures whose conformations are susceptible to temperature changes and behave as primary sensors of temperature. Examples of thermosensory structures include DNA, RNA, specific proteins or lipids from cellular membranes.

Chaperones

Proteins that assist in the correct folding or assembly of other proteins.

Fluorescence recovery after photobleaching

(FRAP). An optical technique for quantifying the kinetics of diffusion or active movement of biological molecules. This method involves labelling a specific cell component with a fluorescent molecule, followed by photobleaching a sharply defined region of the cell. Imaging is used to observe the subsequent rates and patterns of fluorescence recovery.

SWI/SNF

A chromatin-remodelling complex that uses DNA-dependent ATP hydrolysis to mobilize nucleosomes and render the DNA accessible for various nuclear processes. The SWI/SNF complex is required for expression of many inducible genes.

Chromatin immunoprecipitation

(ChIP). A method used to determine whether and where a given protein associates to DNA. This technique is also used to characterize the distribution of specific chromatin marks on the genome.

Mediator

A ~30-subunit co-activator complex that is necessary for successful transcription of class II promoters of metazoan genes. Mediator coordinates the signals between enhancers and the general transcription machinery through its interaction with RNA polymerase II and site-specific factors.

SAGA

The yeast SAGA complex (Spt–Ada–Gcn5–acetyltransferase) is a large, multi-subunit complex containing several enzymatic activities that are linked to activators and histones and involved in core promoter selectivity. SAGA is necessary for turning on genes that respond to stress. It shows a high degree of structural conservation with a human complex: the TATA box binding protein (TBP)-free TAFII-containing complex.

FOS

An oncogene that is activated by diverse stimuli and stresses, including serum growth factors and MAPK cascades. Members of the FOS family can dimerize with JUN proteins to form the activator protein 1 (AP1) transcription factor, which has been involved as a regulator of cell proliferation, differentiation and transformation.

Sumoylation

The post-translational modification of proteins that involves the covalent attachment of a small ubiquitin-like modifier (SUMO) and regulates the interactions of those proteins with other macromolecules.

AU-rich elements

(AREs). Regulatory elements usually located in the 3′UTR of mRNAs that mediate recognition of an array of RNA-binding proteins and are determinant of RNA stability and translation.

Stress granules

Cytoplasmic RNA–protein complexes containing non-translating mRNAs, translation initiation components and other additional proteins that affect mRNA function. Stress granules are induced by stress and affect mRNA translation and stability.

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de Nadal, E., Ammerer, G. & Posas, F. Controlling gene expression in response to stress. Nat Rev Genet 12, 833–845 (2011). https://doi.org/10.1038/nrg3055

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