**5.2 mRNA export**

*Gene Expression and Control*

robustly achieved through different mechanisms.

adapt to the new conditions [31, 45].

**5.1 Transcript/RNA stability**

increasing its activating activity on chromatin remodelers [59]. Apart from chromatin remodelers, MAPKs govern a cohort of histone modifiers that not only destabilize nucleosomes but also, in a more complex manner, generate selective marks that dictate nucleosome dynamics. An example of this type of regulation is the Hog1 dependent gene recruitment of Rpd3, a histone deacetylase, that induces gene expression by promoting the eviction of histones at osmoresponsive genes [60] and the regulation of H3K4 monomethylation to dictate specificity of chromatin remodelers [61]. During elongation, as Hog1 travels with the elongating RNA polymerase, it recruits the RSC remodeling complex, thereby facilitating transcription along the gene body [62]. In mammals, ERKs, p38, and JNK promote the phosphorylation of H3S10 either directly or through their downstream kinases [38, 63]. p38 also phosphorylates the transcription factor MEF2D, which, in turn, leads to recruitment of the Ash2L-containing methyltransferase complex that generates an increase in the activating mark H3K4me3 [64]. These examples highlight the relevance of MAPK-mediated histone modification to generate an efficient chromatin remodeling

MAPKs also regulate gene silencing through chromatin remodelers. ERK1/2 directly interacts with the histone deacetylase 4 (HDAC4) that removes acetyl groups leading to chromatin condensation [6]. Similarly, Hog1 promotes the transcription of *PNC1*, which encodes an activator of Sir2, a histone acetyltransferase that protects sensible rRNA-coding regions from DNA damage [65]. In these two

The ultimate goal of MAPK-mediated transcriptional reprogramming is to change the proteome composition. This change becomes especially important upon extracellular challenge when a massive pool of previously low-abundant RNAs needs to be expressed. Activated MAPKs target mRNA-binding proteins to downregulate unnecessary mRNAs and favor expression of the required genes in order to

Genomic run-on (GRO) experiments that have revealed global changes of gene expression in response to stress are also achieved through the regulation of mRNA stability and decay [66]. In yeast, upon osmotic stress, there is a broad mRNA destabilization, while Hog1 plays a role on the stabilization of osmo-induced mRNAs [67]. The p38 MAPK pathway is also a key regulator of the mRNA stability of both TTP (tristetraprolin), a protein that shortens the half-lives of adenine-uracil rich element (ARE)-containing mRNA, and HuR (human antigen R), a protein that stabilizes such mRNA. The role of p38 turns out to be opposed depending on the cell type [68]. Like p38, ERK and possibly JNK are thought to target HuR, changing its localization to the cytosol, where it stabilizes ARE-containing mRNA [69]. As a further example of the role of p38 in regulating mRNA stability, p38-mediated phosphorylation of ADAR1p110, another mRNA-binding protein, suppresses apoptosis in stressed cells

by protecting many antiapoptotic gene transcripts from mRNA decay [70].

Another layer of transcriptional regulation coordinated by MAPKs, which has gained importance over the years, is the regulation of miRNA biogenesis. A relevant example of the coordination of the regulation of miRNA by different MAPK cascades is the regulation that takes place in the early stages of the inflammatory response. JNK and p38 trigger transcription of the miRNA let-7f, which downregulates the

cases, MAPKs act as repressing elements of chromatin remodeling.

**5. Role of MAPK signaling in post-transcriptional regulation**

**30**

There are numerous examples of interactions between MAPK pathways and different components of the mRNA exporting machinery in biological systems ranging from yeast to mammalian cells. In yeast, it has been reported that, in response to osmotic or heat stress, Hog1 and Mpk1, respectively, phosphorylate components of the nuclear pore complex to increase the export efficiency of stress-responsive mRNAs [72, 73]. Similarly, in mammals, both p38 and ERK pathways regulate RNA-binding proteins such as eIF4E or hDl1 that facilitate mRNA export [74, 75]. In the event of stress, the export of the newly transcribed mRNAs is prioritized to maximize the transcriptional response.
