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Elongating under Stress

Elongating under Stress SAGE-Hindawi Access to Research Genetics Research International Volume 2011, Article ID 326286, 7 pages doi:10.4061/2011/326286 Review Article Eulalia ` de Nadal and Francesc Posas Cell Signaling Unit, Departament de Ci`encies Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), C/ Doctor Aiguader 88, 08003 Barcelona, Spain Correspondence should be addressed to Eulalia ` de Nadal, eulalia.nadal@upf.edu and Francesc Posas, francesc.posas@upf.edu Received 13 June 2011; Accepted 6 July 2011 Academic Editor: Sebastian ´ Chav ´ ez Copyright © 2011 E. de Nadal and F. Posas. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In response to extracellular stimuli, mitogen-activated protein kinases (MAPKs) modulate gene expression to maximize cell survival. Exposure of yeast to high osmolarity results in activation of the p38-related MAPK Hog1, which plays a key role in reprogramming the gene expression pattern required for cell survival upon osmostress. Hog1 not only regulates initiation but also modulates other steps of the transcription process. Recent work indicates that other yeast signalling MAPKs such as Mpk1 modulate transcriptional elongation in response to cell wall stress. Similarly, mammalian MAPKs have also been found associated to coding regions of stress-responsive genes. In this paper, significant progress in MAPK-regulated events that occur during the transcriptional elongation step is summarized, and future directions are discussed. We expect that the principles learned from these studies will provide a new understanding of the regulation of gene expression by signalling kinases. 1. Introduction the yeast cell wall, including elevated growth temperature, pheromone-induced morphogenesis, and chemical cell wall Signal transduction pathways allow cells to sense and antagonist (see Figure 1)[5, 14]. MAPK pathways are known respond to extracellular stimuli. MAPK modules are con- to be conserved during the evolution of the entire eukaryotic served signalling elements utilized in many intracellular kingdom. The Hog1 functional ortholog in mammalian cells signal transduction pathways in eukaryotic organisms [1]. is the p38 family of stress-activated MAPKs (SAPKs) and Each MAPK module is activated by specific types of stimuli responds to several stresses [15, 16]. Mpk1 is a functional to induce specific adaptive response. The central core of homolog of human Erk5 (for extracellular signal-regulated MAPK systems consists of a tier of kinases, a MAPK kinase), which is activated in response to growth factors as kinase kinase (MAPKKK) that phosphorylates and activates a well as various stresses [17]. MAPK kinase (MAPKK) on serine and threonine that in turn In yeast, these two MAPKs play an important role in phosphorylates the MAPK on a threonine (sometimes ser- controlling gene expression, and they both modulate tran- ine) and tyrosine residue. In yeast Saccharomyces cerevisiae, scription initiation and elongation steps of the transcription there are several MAPK cascades (for reviews of function and cycle. We will focus here on the role of Hog1 and Mpk1 in regulation in yeast MAPK signalling, see [2–8]). regulation of transcription elongation. The HOG (high osmolarity glycerol) pathway is activated in response to osmostress by two upstream independent branches that converge on the MAPKK Pbs2, which controls 2. An Overview of Regulation of Transcriptional Hog1 MAPK activity (see Figure 1)[2, 9–11]. Upon stress, Initiation by Hog1 and Mpk1 Hog1 translocated into the nucleus [12, 13]. The CWI (cell wall integrity) pathway, which is comprised of Bck1, Mkk1/2, Among other functions, Hog1 is a master regulator of and the Mpk1/Slt2 (and its pseudokinase paralogue Mlp1) reprogramming gene expression in response to osmostress. MAPK, becomes activated under a number of different Upon stress, the yeast genome alters its expression pattern conditions that compromise the structure and function of up to 20% depending on the strength and duration of the 2 Genetics Research International Osmostress Cell wall stress a noncatalytic mechanism [37, 45–47]. Swi4 forms a complex with Mpk1 upon stress, and it associates with SBF-binding Sensing mechanisms sites in the promoters of cell wall stress target genes [48]. Moreover, Mpk1 regulates Swi6 nucleocytoplasmic shuttling in a biphasic manner: first, formation of the Mpk1-Swi4 Ste11, Ssk2/22 Bck1 MAPKKK complex recruits Swi6 to the nucleus for transcriptional activation and, second, Mpk1 negatively regulates Swi6 by ST phosphorylation, which inhibits nuclear entry [49, 50]. Pbs2 MAPKK Mkk1/2 3. The Hog1 MAPK Regulates TY MAPK Hog1 Transcriptional Elongation Mpk1 (Slt2) The transcription cycle consists of several steps, and elon- gation is a critical phase of transcription susceptible of strong regulation [51–53]. In addition to its association to promoters, Hog1 is also present at coding regions of stress- Adaptive responses Adaptive responses responsive genes, suggesting to have a more general role as chromatin-associated enzyme than previously expected. Figure 1: The HOG and CWI pathways. CWI signalling pathway Actually, genome-wide chromatin binding of the MAPK has is initiated at the plasma membrane through different sensing revealed that Hog1 is recruited to most of the transcribed mechanisms and is activated by Pkc1 upon different cell wall stresses. The linear cascade consists in the Bck1 MAPKKK, which regions of osmoinducible genes [26, 27]. Moreover, it activates a pair of redundant MAPKK (Mkk1 and Mkk2) that is recruited to transcribed regions independently of the in turn activates the Mpk1/Stl2 MAPK. In the HOG pathway, promoter bound-specific transcription factors dedicated two independent upstream osmosensing mechanisms lead to the to osmostress adaptation. By uncoupling Hog1-dependent activation of the MAPKKK Ste11 and Ssk2/22. The Pbs2 MAPKK transcription initiation from transcription elongation, it has integrates both signals and activates the Hog1 MAPK. Both been demonstrated that binding of Hog1 to stress-responsive the HOG and CWI pathways are involved in the regulation of coding regions depends on the 3 UTR regions. However, how transcriptional elongation by specific types of stimuli to induce SAPK is recruited to these specific 3 regions in response to specific adaptive response. stress remains so far unknown [31]. Which are the tasks of Hog1 at coding regions is still an stress [18–24]. A major part of these changes are regulated by open question. Recruitment of the kinase to the open reading Hog1 through several unrelated transcription factors such as frames (ORFs) is essential for an increased association of Msn2/4, Hot1, Smp1, or Sko1, which work in combination RNA Pol II and proper mRNA production in response to at the specific stress-dependent promoters [19, 21, 25–28]. osmostress [31]. Moreover, Hog1 interacts with elongating Recently, it has been reported the dynamics of binding of RNA Pol II (phosphorylated at serine 2 and 5 of the C- these transcription factors to their target genes in response terminal domain) as well as with general components of to osmostress [19, 25]. The integration of this analysis the transcription elongation complex. It is worth noting with gene expression patterns reveals a complex dynamic that the catalytic activity of Hog1 is required both for its and hierarchical network in which specific combinations of binding to chromatin and to stimulate mRNA production transcription factors activate distinct sets of genes at discrete during the elongation process. However, the identification times to coordinate a rapid and transient stress-adaptive of phosphorylation events mediated by the MAPK during response [25]. It is well known that, when transcription is transcription elongation remains open. initiated in response to osmostress, the MAPK is recruited Binding of Hog1 to the stress-responsive ORFs is re- to the osmoresponsive genes by specific transcription factors stricted temporally. Although the initial recruitment of the [26, 27, 29–31] and directly phosphorylates some of them MAPK and RNA Pol II is similar, Pol II association is [32–34]. Once bound to chromatin, Hog1 serves as a observed for a longer period upon osmostress, whereas platform to recruit the RNA Pol II [32] and associated binding of Hog1 is restricted at the initial phase of elongation general transcription factors such as the Mediator or SAGA [31]. This suggests a role for the MAPK at early stages of the [30, 35] as well as histone-modifying factors [36]. It is worth elongation process. Chromatin structure is tightly regulated noting that Hog1 is not the unique kinase that binds to through multiple mechanisms, including chromatin remod- chromatin. Actually, most MAPKs in yeast associate with elling, histone variant incorporation, histone eviction, and genes that are their targets of transcriptional control [27, 37]. histone modification [54–56]. Actually, several genome-wide Further details in the regulation of transcriptional initiation studies found a significant loss of histones from the promoter by MAPKs and their implications for understanding control and coding regions of heavily transcribed genes throughout of gene expression are described in [38–40]. the genome [57]. In response to cell wall stress, two known transcription Nucleosome positioning of stress-responsive loci is factors, Rlm1 and SBF (Swi4 and Swi6), are controlled by altered dramatically in a Hog1 MAPK-dependent manner Mpk1 by different mechanisms. Whereas Rlm1 is activated during osmostress [58]. Hog1 physically interacts with the through direct phosphorylation [41–44], SBF is activated by RSC chromatin remodelling complex to direct its association Genetics Research International 3 with the coding regions of osmoresponsive genes and in transcription elongation is to prevent such premature allow for nucleosome rearrangements during transcriptional termination under inducing conditions. Indeed, Mpk1- elongation upon stress. In the RSC mutants, RNA Pol II accu- Paf1 interaction blocks recruitment of the Sen1-Nrd1-Nab3 mulates on stress-dependent promoters but not in coding termination complex to allow effective elongation of cell- regions. Moreover, the RSC mutants display reduced stress wall stress genes [49]. Therefore, it is becoming increasingly gene expression and enhanced sensitivity to osmostress [58]. apparent that yeast MAPKs play a key role in regulation Other chromatin remodelling complexes such as INO80 of transcriptional elongation in response to cellular stress associated with the ORFs of stress genes in a stress-specific although the molecular mechanisms involved differ among way [59, 60]. Mutants defective in subunits of the INO80 kinases. complex, as well as in several histone chaperone systems, lead to globally increased transcript levels upon osmostress and delayed repositioning of histones in ORF regions of stress 5. MAPK Signalling and Transcriptional genes. Thus, it seems that INO80 is relevant for the efficient Elongation in Higher Eukaryotes downregulation of stress genes under acute stress conditions. Single-cell experiments have shown that Hog1 nuclear Binding of signalling kinases to chromatin has been now accumulation increases linearly with stimulus. However, shown in organisms other than yeast. Several reports support at low stress levels, the transcriptional output shows two an essential role of p38 MAPK in the regulation of tran- distinct subpopulations, one responding and the other one scription upon inflammation and stress responses [67, 68] not. Of note, this bimodality is reflected in chromatin as well as during cell growth and differentiation [69–71]. remodelling and depends on both the retention time and In response to stress, p38 associates to chromatin as Hog1 concentration of Hog1 in the nucleus [61]. Thus, chro- does in yeast and allows for recruitment of RNA Pol II and matin dynamics, together with transient MAPK activation, transcriptional initiation. Similarly, anchoring of active p38 determines a transcriptional threshold in response to linear to target stress-dependent promoters is mediated by specific increase in signalling upon stress. transcription factors [72]. Moreover, p38 is also present at coding regions depending on its activity upon stress, clearly suggesting that it might be travelling along with the nascent 4. The Mpk1 MAPK Serves in mRNA elongating machinery in a similar way as described in Transcription Elongation yeast [72]. Actually, it is described that the MAPK interacts with the RNA Pol II in mammalian cells [32]. The role of MAPK in the modulation of transcriptional p38 controls skeletal muscle differentiation by regulating elongation is not restricted to Hog1. Other yeast signalling the sequential activation of myogenic regulatory factors kinases, such as Fus3, PKA, or Mpk1, have been reported and their transcriptional coactivators, including chromatin to associate to coding regions of activated genes [62]. Mpk1 remodelling enzymes (reviewed in [73]). However, whether associates with the coding region of the FKS2 gene in the MAPK has a specific role during transcriptional elonga- response to cell wall stress although such binding does not tion in muscle differentiation remains to be determined. require MAPK kinase activity [49]. This diverges from Hog1, The extracellular signal-regulated kinase (ERK) pathway where catalytic activity is essential for kinase recruitment. also regulates gene expression. Erk1 is activated by proges- How does Mpk1 associate with the FKS2 coding region terone and phosphorylates the progesterone receptor. Then, during transcription? Mpk1 is tethered to the elongation a complex of activated progesterone receptor, Erk1, and its complex through its interaction with RNA Pol II-associated target kinase Msk1 is recruited to the target promoters, where complex Paf1C complex [49, 63, 64]. Paf1 subunit interacts Msk1 phosphorylates histone H3 at serine 10 promoting directly with Mpk1 through its docking motif (D-motif) chromatin remodelling and gene regulation (reviewed in in a cell wall stress-dependent manner. Interaction between [74, 75]). Once more, the specific role of the Erk1 kinase in both proteins requires the Swi4 and Swi6 but not Rlm1 transcriptional elongation in response to progestins remains transcription initiation factor. The paf1-4A mutant, which is to be elucidated. unable to interact with Mpk1, is deficient for transcription When expressed in yeast, the human Erk5 MAPK is elongation of the FKS2 gene and renders cells sensitive to activated in response to cell wall stress and suppresses the cell wall stress. Actually, in this mutant, Mpk1 is recruited phenotypic defects of a mpk1 mutant. Moreover, Erk5 is able to the promoter but does not progress into the coding to activate gene expression through Rlm1 as well as SBF region of FKS2 in response to stress [49]. This is again a transcription factors [17, 37]. There are evidences suggesting different scenario when compared to Hog1 and osmostress, that MAPK regulation of Paf1C function is conserved in since Mpk1 is moving from the initiation to the elonga- humans. Actually, Erk5 can interact with a predicted D-motif tion complexes using the Paf1 complex as a scaffold. Of in the human PD2/PAF1 within the same region as that note, Paf1 and Hog1 are able to coimmunoprecipitate in found in yeast Paf1 to drive transcription elongation [47]. response to osmostress [31] if such interaction is through the D-motif in Paf1 remains to be elucidated. A large Therefore, it is likely that MAPK regulation of tran- number of short sense transcripts across the FKS2 promoter- scription in higher eukaryotes is not restricted to initiation proximal region terminate under noninducing conditions but also to elongation upon stress and that MAPK-driven [65, 66]. The critical function of the Mpk1-Paf1 association mechanisms are conserved among eukaryotic cells. 4 Genetics Research International 6. Conclusions Sen1 Nab3 Proper adaptation to stress is critical for cell survival. Nrd1 There has been a number of signalling networks involved in stress signal transduction, and, amongst them, MAPK Mpk1 Mpk1 Paf1 Paf1 signalling networks stand out. One important piece of the Mpk1 Swi6 different adaptive strategies consists of a massive reorga- Pol II/TEF Pol II/TEF Swi4 nization of the gene expression capacity. Protein kinases Promoter ORF 3 UTR not only phosphorylate target proteins, but also themselves become part of the transcriptional complex. This suggests a new scenario in which signalling kinases, rather than Cell wall stress-responsive gene (FKS2) simply relaying the signal to the transcriptional effectors, may function as integral components of the transcriptional complexes that activate expression of distinct target genes (see Figure 2). Actually, several recent reports have shown Pol II Hog1 Hog1 that the role of MAPK in the regulation of the transcription RSC Hog1 Pol II/TEF TF cycle is not limited to transcription initiation but rather extends to the process of transcriptional elongation. For Promoter ORF 3 UTR instance, the Hog1 MAPK fits with the description of a bona fide elongation factor, with the feature that its role Osmostress-responsive gene in elongation is restricted to osmoresponsive genes, and it has a pivotal role in nucleosome remodelling upon stress. Figure 2: Regulation of transcriptional elongation by MAPK Moreover, other MAPKs such as Mpk1 block premature signalling pathways. Mpk1 and Hog1 MAPKs are key regulators transcription termination of stress-induced genes. Further of transcription in response to specific stresses. Whereas activated studies are required to establish whether the mechanisms by Mpk1 is moving from initiation to elongation complexes through its interaction with Paf1C complex, binding of Hog1 to the ORFs which Hog1 and Mpk1 regulate transcriptional elongation seems to be dependent on the 3 UTR region of the osmoresponsive are conserved in both MAPKs. gene. Association of Mpk1 with Paf1 serves as an antitermination We are just beginning to understand the overlapping factor by blocking recruitment of the Sen1-Nrd1-Nab3 termination link between signal transduction pathways and modulation complex to the cell wall stress-responsive gene. Hog1 acts as a stress- of transcriptional elongation. The molecular mechanisms specific transcription elongation factor (TEF) and targets selectively of such relationship are far from fully being understood. the RSC complex to osmoinducible ORFs, which displaces nucleo- For example, one unresolved question is how the MAPK somes contributing to the efficient activation of transcription. Hog1 is recruited specifically to the osmo-responsive coding regions. Is there some special feature in the 3 UTR region Acknowledgments of stress-dependent genes targeting the kinase? or is there some transcription elongation factor that specifically recruits The authors thank all the members of the Cell Signaling the kinase? Another key question remaining in the field is Unit. They apologize to colleagues whose work could not be which are the phosphorylation events mediated by MAPK cited due to size limitation. The laboratory of F. Posas and E. on the transcriptional elongation machinery. Although it is de Nadal is being supported by Fundacion ´ Marcelino Bot´ın clear that there are noncatalytic functions in transcription (FMB), Ministerio de Ciencia ´ y Innovacion, ´ BFU program regulation by MAPK, activity of Hog1 is needed for the (BFU2008-00530 to E. de Nadal and BIO2009-07762 to recruitment of the kinase onto the promoters and coding F. Posas), Consolider Ingenio 2010 programme (Grant regions of osmostress-responsive genes. Recent findings shed no. CSD2007-0015), and FP7 (UNICELLSYS)framework light on the link between upstream signalling kinases and programs. F. Posas is recipient of an ICREA Academia ` direct phosphorylation of histones and/or histone mod- (Generalitat de Catalunya). ifiers (reviewed in [76]). Moreover, transcriptional stress responses and the chromatin structure are tightly linked [77, References 78]. Why regulation of Paf1 by Mpk1 only affects those cell wall stress-activated genes that are under the control of the [1] C. Widmann, S. Gibson, M. 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Elongating under Stress

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Copyright © 2011 Eulàlia de Nadal and Francesc Posas. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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SAGE-Hindawi Access to Research Genetics Research International Volume 2011, Article ID 326286, 7 pages doi:10.4061/2011/326286 Review Article Eulalia ` de Nadal and Francesc Posas Cell Signaling Unit, Departament de Ci`encies Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), C/ Doctor Aiguader 88, 08003 Barcelona, Spain Correspondence should be addressed to Eulalia ` de Nadal, eulalia.nadal@upf.edu and Francesc Posas, francesc.posas@upf.edu Received 13 June 2011; Accepted 6 July 2011 Academic Editor: Sebastian ´ Chav ´ ez Copyright © 2011 E. de Nadal and F. Posas. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In response to extracellular stimuli, mitogen-activated protein kinases (MAPKs) modulate gene expression to maximize cell survival. Exposure of yeast to high osmolarity results in activation of the p38-related MAPK Hog1, which plays a key role in reprogramming the gene expression pattern required for cell survival upon osmostress. Hog1 not only regulates initiation but also modulates other steps of the transcription process. Recent work indicates that other yeast signalling MAPKs such as Mpk1 modulate transcriptional elongation in response to cell wall stress. Similarly, mammalian MAPKs have also been found associated to coding regions of stress-responsive genes. In this paper, significant progress in MAPK-regulated events that occur during the transcriptional elongation step is summarized, and future directions are discussed. We expect that the principles learned from these studies will provide a new understanding of the regulation of gene expression by signalling kinases. 1. Introduction the yeast cell wall, including elevated growth temperature, pheromone-induced morphogenesis, and chemical cell wall Signal transduction pathways allow cells to sense and antagonist (see Figure 1)[5, 14]. MAPK pathways are known respond to extracellular stimuli. MAPK modules are con- to be conserved during the evolution of the entire eukaryotic served signalling elements utilized in many intracellular kingdom. The Hog1 functional ortholog in mammalian cells signal transduction pathways in eukaryotic organisms [1]. is the p38 family of stress-activated MAPKs (SAPKs) and Each MAPK module is activated by specific types of stimuli responds to several stresses [15, 16]. Mpk1 is a functional to induce specific adaptive response. The central core of homolog of human Erk5 (for extracellular signal-regulated MAPK systems consists of a tier of kinases, a MAPK kinase), which is activated in response to growth factors as kinase kinase (MAPKKK) that phosphorylates and activates a well as various stresses [17]. MAPK kinase (MAPKK) on serine and threonine that in turn In yeast, these two MAPKs play an important role in phosphorylates the MAPK on a threonine (sometimes ser- controlling gene expression, and they both modulate tran- ine) and tyrosine residue. In yeast Saccharomyces cerevisiae, scription initiation and elongation steps of the transcription there are several MAPK cascades (for reviews of function and cycle. We will focus here on the role of Hog1 and Mpk1 in regulation in yeast MAPK signalling, see [2–8]). regulation of transcription elongation. The HOG (high osmolarity glycerol) pathway is activated in response to osmostress by two upstream independent branches that converge on the MAPKK Pbs2, which controls 2. An Overview of Regulation of Transcriptional Hog1 MAPK activity (see Figure 1)[2, 9–11]. Upon stress, Initiation by Hog1 and Mpk1 Hog1 translocated into the nucleus [12, 13]. The CWI (cell wall integrity) pathway, which is comprised of Bck1, Mkk1/2, Among other functions, Hog1 is a master regulator of and the Mpk1/Slt2 (and its pseudokinase paralogue Mlp1) reprogramming gene expression in response to osmostress. MAPK, becomes activated under a number of different Upon stress, the yeast genome alters its expression pattern conditions that compromise the structure and function of up to 20% depending on the strength and duration of the 2 Genetics Research International Osmostress Cell wall stress a noncatalytic mechanism [37, 45–47]. Swi4 forms a complex with Mpk1 upon stress, and it associates with SBF-binding Sensing mechanisms sites in the promoters of cell wall stress target genes [48]. Moreover, Mpk1 regulates Swi6 nucleocytoplasmic shuttling in a biphasic manner: first, formation of the Mpk1-Swi4 Ste11, Ssk2/22 Bck1 MAPKKK complex recruits Swi6 to the nucleus for transcriptional activation and, second, Mpk1 negatively regulates Swi6 by ST phosphorylation, which inhibits nuclear entry [49, 50]. Pbs2 MAPKK Mkk1/2 3. The Hog1 MAPK Regulates TY MAPK Hog1 Transcriptional Elongation Mpk1 (Slt2) The transcription cycle consists of several steps, and elon- gation is a critical phase of transcription susceptible of strong regulation [51–53]. In addition to its association to promoters, Hog1 is also present at coding regions of stress- Adaptive responses Adaptive responses responsive genes, suggesting to have a more general role as chromatin-associated enzyme than previously expected. Figure 1: The HOG and CWI pathways. CWI signalling pathway Actually, genome-wide chromatin binding of the MAPK has is initiated at the plasma membrane through different sensing revealed that Hog1 is recruited to most of the transcribed mechanisms and is activated by Pkc1 upon different cell wall stresses. The linear cascade consists in the Bck1 MAPKKK, which regions of osmoinducible genes [26, 27]. Moreover, it activates a pair of redundant MAPKK (Mkk1 and Mkk2) that is recruited to transcribed regions independently of the in turn activates the Mpk1/Stl2 MAPK. In the HOG pathway, promoter bound-specific transcription factors dedicated two independent upstream osmosensing mechanisms lead to the to osmostress adaptation. By uncoupling Hog1-dependent activation of the MAPKKK Ste11 and Ssk2/22. The Pbs2 MAPKK transcription initiation from transcription elongation, it has integrates both signals and activates the Hog1 MAPK. Both been demonstrated that binding of Hog1 to stress-responsive the HOG and CWI pathways are involved in the regulation of coding regions depends on the 3 UTR regions. However, how transcriptional elongation by specific types of stimuli to induce SAPK is recruited to these specific 3 regions in response to specific adaptive response. stress remains so far unknown [31]. Which are the tasks of Hog1 at coding regions is still an stress [18–24]. A major part of these changes are regulated by open question. Recruitment of the kinase to the open reading Hog1 through several unrelated transcription factors such as frames (ORFs) is essential for an increased association of Msn2/4, Hot1, Smp1, or Sko1, which work in combination RNA Pol II and proper mRNA production in response to at the specific stress-dependent promoters [19, 21, 25–28]. osmostress [31]. Moreover, Hog1 interacts with elongating Recently, it has been reported the dynamics of binding of RNA Pol II (phosphorylated at serine 2 and 5 of the C- these transcription factors to their target genes in response terminal domain) as well as with general components of to osmostress [19, 25]. The integration of this analysis the transcription elongation complex. It is worth noting with gene expression patterns reveals a complex dynamic that the catalytic activity of Hog1 is required both for its and hierarchical network in which specific combinations of binding to chromatin and to stimulate mRNA production transcription factors activate distinct sets of genes at discrete during the elongation process. However, the identification times to coordinate a rapid and transient stress-adaptive of phosphorylation events mediated by the MAPK during response [25]. It is well known that, when transcription is transcription elongation remains open. initiated in response to osmostress, the MAPK is recruited Binding of Hog1 to the stress-responsive ORFs is re- to the osmoresponsive genes by specific transcription factors stricted temporally. Although the initial recruitment of the [26, 27, 29–31] and directly phosphorylates some of them MAPK and RNA Pol II is similar, Pol II association is [32–34]. Once bound to chromatin, Hog1 serves as a observed for a longer period upon osmostress, whereas platform to recruit the RNA Pol II [32] and associated binding of Hog1 is restricted at the initial phase of elongation general transcription factors such as the Mediator or SAGA [31]. This suggests a role for the MAPK at early stages of the [30, 35] as well as histone-modifying factors [36]. It is worth elongation process. Chromatin structure is tightly regulated noting that Hog1 is not the unique kinase that binds to through multiple mechanisms, including chromatin remod- chromatin. Actually, most MAPKs in yeast associate with elling, histone variant incorporation, histone eviction, and genes that are their targets of transcriptional control [27, 37]. histone modification [54–56]. Actually, several genome-wide Further details in the regulation of transcriptional initiation studies found a significant loss of histones from the promoter by MAPKs and their implications for understanding control and coding regions of heavily transcribed genes throughout of gene expression are described in [38–40]. the genome [57]. In response to cell wall stress, two known transcription Nucleosome positioning of stress-responsive loci is factors, Rlm1 and SBF (Swi4 and Swi6), are controlled by altered dramatically in a Hog1 MAPK-dependent manner Mpk1 by different mechanisms. Whereas Rlm1 is activated during osmostress [58]. Hog1 physically interacts with the through direct phosphorylation [41–44], SBF is activated by RSC chromatin remodelling complex to direct its association Genetics Research International 3 with the coding regions of osmoresponsive genes and in transcription elongation is to prevent such premature allow for nucleosome rearrangements during transcriptional termination under inducing conditions. Indeed, Mpk1- elongation upon stress. In the RSC mutants, RNA Pol II accu- Paf1 interaction blocks recruitment of the Sen1-Nrd1-Nab3 mulates on stress-dependent promoters but not in coding termination complex to allow effective elongation of cell- regions. Moreover, the RSC mutants display reduced stress wall stress genes [49]. Therefore, it is becoming increasingly gene expression and enhanced sensitivity to osmostress [58]. apparent that yeast MAPKs play a key role in regulation Other chromatin remodelling complexes such as INO80 of transcriptional elongation in response to cellular stress associated with the ORFs of stress genes in a stress-specific although the molecular mechanisms involved differ among way [59, 60]. Mutants defective in subunits of the INO80 kinases. complex, as well as in several histone chaperone systems, lead to globally increased transcript levels upon osmostress and delayed repositioning of histones in ORF regions of stress 5. MAPK Signalling and Transcriptional genes. Thus, it seems that INO80 is relevant for the efficient Elongation in Higher Eukaryotes downregulation of stress genes under acute stress conditions. Single-cell experiments have shown that Hog1 nuclear Binding of signalling kinases to chromatin has been now accumulation increases linearly with stimulus. However, shown in organisms other than yeast. Several reports support at low stress levels, the transcriptional output shows two an essential role of p38 MAPK in the regulation of tran- distinct subpopulations, one responding and the other one scription upon inflammation and stress responses [67, 68] not. Of note, this bimodality is reflected in chromatin as well as during cell growth and differentiation [69–71]. remodelling and depends on both the retention time and In response to stress, p38 associates to chromatin as Hog1 concentration of Hog1 in the nucleus [61]. Thus, chro- does in yeast and allows for recruitment of RNA Pol II and matin dynamics, together with transient MAPK activation, transcriptional initiation. Similarly, anchoring of active p38 determines a transcriptional threshold in response to linear to target stress-dependent promoters is mediated by specific increase in signalling upon stress. transcription factors [72]. Moreover, p38 is also present at coding regions depending on its activity upon stress, clearly suggesting that it might be travelling along with the nascent 4. The Mpk1 MAPK Serves in mRNA elongating machinery in a similar way as described in Transcription Elongation yeast [72]. Actually, it is described that the MAPK interacts with the RNA Pol II in mammalian cells [32]. The role of MAPK in the modulation of transcriptional p38 controls skeletal muscle differentiation by regulating elongation is not restricted to Hog1. Other yeast signalling the sequential activation of myogenic regulatory factors kinases, such as Fus3, PKA, or Mpk1, have been reported and their transcriptional coactivators, including chromatin to associate to coding regions of activated genes [62]. Mpk1 remodelling enzymes (reviewed in [73]). However, whether associates with the coding region of the FKS2 gene in the MAPK has a specific role during transcriptional elonga- response to cell wall stress although such binding does not tion in muscle differentiation remains to be determined. require MAPK kinase activity [49]. This diverges from Hog1, The extracellular signal-regulated kinase (ERK) pathway where catalytic activity is essential for kinase recruitment. also regulates gene expression. Erk1 is activated by proges- How does Mpk1 associate with the FKS2 coding region terone and phosphorylates the progesterone receptor. Then, during transcription? Mpk1 is tethered to the elongation a complex of activated progesterone receptor, Erk1, and its complex through its interaction with RNA Pol II-associated target kinase Msk1 is recruited to the target promoters, where complex Paf1C complex [49, 63, 64]. Paf1 subunit interacts Msk1 phosphorylates histone H3 at serine 10 promoting directly with Mpk1 through its docking motif (D-motif) chromatin remodelling and gene regulation (reviewed in in a cell wall stress-dependent manner. Interaction between [74, 75]). Once more, the specific role of the Erk1 kinase in both proteins requires the Swi4 and Swi6 but not Rlm1 transcriptional elongation in response to progestins remains transcription initiation factor. The paf1-4A mutant, which is to be elucidated. unable to interact with Mpk1, is deficient for transcription When expressed in yeast, the human Erk5 MAPK is elongation of the FKS2 gene and renders cells sensitive to activated in response to cell wall stress and suppresses the cell wall stress. Actually, in this mutant, Mpk1 is recruited phenotypic defects of a mpk1 mutant. Moreover, Erk5 is able to the promoter but does not progress into the coding to activate gene expression through Rlm1 as well as SBF region of FKS2 in response to stress [49]. This is again a transcription factors [17, 37]. There are evidences suggesting different scenario when compared to Hog1 and osmostress, that MAPK regulation of Paf1C function is conserved in since Mpk1 is moving from the initiation to the elonga- humans. Actually, Erk5 can interact with a predicted D-motif tion complexes using the Paf1 complex as a scaffold. Of in the human PD2/PAF1 within the same region as that note, Paf1 and Hog1 are able to coimmunoprecipitate in found in yeast Paf1 to drive transcription elongation [47]. response to osmostress [31] if such interaction is through the D-motif in Paf1 remains to be elucidated. A large Therefore, it is likely that MAPK regulation of tran- number of short sense transcripts across the FKS2 promoter- scription in higher eukaryotes is not restricted to initiation proximal region terminate under noninducing conditions but also to elongation upon stress and that MAPK-driven [65, 66]. The critical function of the Mpk1-Paf1 association mechanisms are conserved among eukaryotic cells. 4 Genetics Research International 6. Conclusions Sen1 Nab3 Proper adaptation to stress is critical for cell survival. Nrd1 There has been a number of signalling networks involved in stress signal transduction, and, amongst them, MAPK Mpk1 Mpk1 Paf1 Paf1 signalling networks stand out. One important piece of the Mpk1 Swi6 different adaptive strategies consists of a massive reorga- Pol II/TEF Pol II/TEF Swi4 nization of the gene expression capacity. Protein kinases Promoter ORF 3 UTR not only phosphorylate target proteins, but also themselves become part of the transcriptional complex. This suggests a new scenario in which signalling kinases, rather than Cell wall stress-responsive gene (FKS2) simply relaying the signal to the transcriptional effectors, may function as integral components of the transcriptional complexes that activate expression of distinct target genes (see Figure 2). Actually, several recent reports have shown Pol II Hog1 Hog1 that the role of MAPK in the regulation of the transcription RSC Hog1 Pol II/TEF TF cycle is not limited to transcription initiation but rather extends to the process of transcriptional elongation. For Promoter ORF 3 UTR instance, the Hog1 MAPK fits with the description of a bona fide elongation factor, with the feature that its role Osmostress-responsive gene in elongation is restricted to osmoresponsive genes, and it has a pivotal role in nucleosome remodelling upon stress. Figure 2: Regulation of transcriptional elongation by MAPK Moreover, other MAPKs such as Mpk1 block premature signalling pathways. Mpk1 and Hog1 MAPKs are key regulators transcription termination of stress-induced genes. Further of transcription in response to specific stresses. Whereas activated studies are required to establish whether the mechanisms by Mpk1 is moving from initiation to elongation complexes through its interaction with Paf1C complex, binding of Hog1 to the ORFs which Hog1 and Mpk1 regulate transcriptional elongation seems to be dependent on the 3 UTR region of the osmoresponsive are conserved in both MAPKs. gene. Association of Mpk1 with Paf1 serves as an antitermination We are just beginning to understand the overlapping factor by blocking recruitment of the Sen1-Nrd1-Nab3 termination link between signal transduction pathways and modulation complex to the cell wall stress-responsive gene. Hog1 acts as a stress- of transcriptional elongation. The molecular mechanisms specific transcription elongation factor (TEF) and targets selectively of such relationship are far from fully being understood. the RSC complex to osmoinducible ORFs, which displaces nucleo- For example, one unresolved question is how the MAPK somes contributing to the efficient activation of transcription. Hog1 is recruited specifically to the osmo-responsive coding regions. Is there some special feature in the 3 UTR region Acknowledgments of stress-dependent genes targeting the kinase? or is there some transcription elongation factor that specifically recruits The authors thank all the members of the Cell Signaling the kinase? Another key question remaining in the field is Unit. They apologize to colleagues whose work could not be which are the phosphorylation events mediated by MAPK cited due to size limitation. The laboratory of F. Posas and E. on the transcriptional elongation machinery. Although it is de Nadal is being supported by Fundacion ´ Marcelino Bot´ın clear that there are noncatalytic functions in transcription (FMB), Ministerio de Ciencia ´ y Innovacion, ´ BFU program regulation by MAPK, activity of Hog1 is needed for the (BFU2008-00530 to E. de Nadal and BIO2009-07762 to recruitment of the kinase onto the promoters and coding F. Posas), Consolider Ingenio 2010 programme (Grant regions of osmostress-responsive genes. Recent findings shed no. CSD2007-0015), and FP7 (UNICELLSYS)framework light on the link between upstream signalling kinases and programs. F. Posas is recipient of an ICREA Academia ` direct phosphorylation of histones and/or histone mod- (Generalitat de Catalunya). ifiers (reviewed in [76]). Moreover, transcriptional stress responses and the chromatin structure are tightly linked [77, References 78]. Why regulation of Paf1 by Mpk1 only affects those cell wall stress-activated genes that are under the control of the [1] C. Widmann, S. Gibson, M. 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