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

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 adapt to the new conditions [31, 45].

## **5.1 Transcript/RNA stability**

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

**31**

*Shaping the Transcriptional Landscape through MAPK Signaling*

pathways to achieve a finely tuned transcriptional response.

expression of Blimp1 and PRDM1, two transcriptional repressors of inflammatory genes. Since a sustained expression of inflammatory genes is detrimental, later activation of ERK promotes the transcription of Lin28, an inhibitor of let-7f biogenesis, thereby increasing the expression of the Blimp1 and PRDM1 repressors [71]. Here, the same stimuli generate a time-dependent regulated activation of multiple signaling

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

The transcriptional response to external stimuli generates an outburst of mRNAs that have to be spliced. The associations between splicing events that modulate MAPK genes are becoming increasingly relevant in human disease [76]. One strategy to regulate splicing under stress is phosphorylation of the splicing factor TDP-43 by MEK1/2, which prevents TDP-43 aggregation [77]. Another mechanism of regulating splicing is by interfering with the localization of splicing factors such

Translation plays a pivotal role in the control of gene expression and is tightly regulated by MAPK pathways that modulate the activity of several components within the translational machinery [81]. In yeast, Hog1 promotes Rck2-mediated attenuation of protein synthesis in response to osmotic stress by phosphorylation of the translation elongation factor 2 (EF-2) [82]. ERK- and p38-activated MNKs phosphorylate the elongation initiation factor eIF4E to enhance translation initiation [83]. Another example is the activation of RSK, a downstream kinase of ERK. RSK phosphorylates S6, a component of the 40S ribosomal subunit, as well as the elongation initiation factor eIF4B, which facilitates their binding to eIF3 to promote mRNA translation [84, 85]. Besides the targeting of newly transcribed mRNAs, translation regulation can also target mRNAs that have not been transcrip-

tionally induced, a type of regulation found in yeast and mammals [86].

Due to their master regulatory role, MAPKs have sparked a lot of interest and have been the main focus of multiple researchers worldwide over the last 30 years. As MAPK knowledge advances, it has become obvious that the external control of MAPK activity has the potential to modulate cellular behavior and survival. Moreover, MAPK signaling has been found to be altered or defective in many human diseases such as cancer; therefore, achievement of the control of

*DOI: http://dx.doi.org/10.5772/intechopen.80634*

maximize the transcriptional response.

as RNM4, hn-RNPA1, or hSlut7 [78–80].

**6. Future perspectives and challenges**

**5.2 mRNA export**

**5.3 mRNA splicing**

**5.4 Translation**

expression of Blimp1 and PRDM1, two transcriptional repressors of inflammatory genes. Since a sustained expression of inflammatory genes is detrimental, later activation of ERK promotes the transcription of Lin28, an inhibitor of let-7f biogenesis, thereby increasing the expression of the Blimp1 and PRDM1 repressors [71]. Here, the same stimuli generate a time-dependent regulated activation of multiple signaling pathways to achieve a finely tuned transcriptional response.
