Elongating under Stress

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

Shaping the Transcriptional Landscape through MAPK Signaling

A change in the transcriptional landscape is an equilibrium-breaking event important for many biological processes. Mitogen-activated protein kinase (MAPK) signaling pathways are dedicated to sensing extracellular cues and are highly conserved across eukaryotes. Modulation of gene expression in response to the extracellular environment is one of the main mechanisms by which MAPK regulates proteome homeostasis to orchestrate adaptive responses that determine cell fate. A massive body of knowledge generated from population and single-cell analyses has led to an understanding of how MAPK pathways operate. MAPKs have thus emerged as fundamental transcriptome regulators that function through a multi-layered control of gene expression, a process often deregulated in disease, which therefore provides an attractive target for therapeutic strategies. Here, we summarize the current understanding of the mechanisms underlying MAPK-mediated gene expression in organisms ranging from yeast to mammals

Control of Ubp3 ubiquitin protease activity by the Hog1 SAPK modulates transcription upon osmostress

Here, the Hog1 kinase interacts with and activates the ubiquitin protease Ubp3 in a stress-dependent manner. The phosphorylation of Ubp3 enhances RNA polymerase II occupancy on osmotic stress-responsive genes

Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program

Background Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Methods Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Results Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. Conclusions We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma

An RB insensitive to CDK regulation

The N-term phosphorylation of Retinoblastoma (RB) by the p38 stress-activated protein kinase (SAPK) makes RB insensitive to cyclin-dependent kinase (CDK)-Cyclin inhibition, which enhances the transcriptional repression of E2F-driven promoters and delays tumor cell growth. This novel mechanism of RB regulation opens up a window for developing new cancer drug treatments for tumors harboring high CDK-Cyclin activity and a wild-type RB gene

The HOG pathway and the regulation of osmoadaptive responses in yeast

Cells coordinate intracellular activities in response to changes in the extracellular environment to maximize their probability of survival and proliferation. Eukaryotic cells need to adapt to constant changes in the osmolarity of their environment. In yeast, the high-osmolarity glycerol (HOG) pathway is responsible for the response to high osmolarity. Activation of the Hog1 stress-activated protein kinase (SAPK) induces a complex program required for cellular adaptation that includes temporary arrest of cell cycle progression, adjustment of transcription and translation patterns, and the regulation of metabolism, including the synthesis and retention of the compatible osmolyte glycerol. Hog1 is a member of the family of p38 SAPKs, which are present across eukaryotes. Many of the properties of the HOG pathway and downstream-regulated proteins are conserved from yeast to mammals. This review addresses the global view of this signaling pathway in yeast, as well as the contribution of Dr Hohmann's group to its understanding.The laboratories of FP and EdN are supported by grants from the Ministry of Science, Innovation and Universities (PGC2018-094136-B-I00 to FP; BFU2017-85152-P and FEDER to EdN) and the Government of Catalonia (2017 SGR 799). We gratefully acknowledge institutional funding from the Ministry of Science, Innovation and Universities through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme of the Government of Catalonia and the Unidad de Excelencia María de Maeztu, funded by the AEI (CEX2018-000792-M). FP and EdN are recipients of ICREA Acadèmia awards (Government of Catalonia)

Osmostress-induced gene expression--a model to understand how stress-activated protein kinases (SAPKs) regulate transcription

Adaptation is essential for maximizing cell survival and for cell fitness in response to sudden changes in the environment. Several aspects of cell physiology change during adaptation. Major changes in gene expression are associated with cell exposure to environmental changes, and several aspects of mRNA biogenesis appear to be targeted by signaling pathways upon stress. Exhaustive reviews have been written regarding adaptation to stress and regulation of gene expression. In this review, using osmostress in yeast as a prototypical case study, we highlight those aspects of regulation of gene induction that are general to various environmental stresses as well as mechanistic aspects that are potentially conserved from yeast to mammals.The laboratory of F.P. and E.N. is supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2012-33503 and FEDER, BFU2014-52125-REDT and BFU2014-51672-REDC to F.P. and BFU2014-52333-P to E.N.), the Catalan Government (2014 SGR 599) and an ERC Advanced Grant (number 294294) from the EU seventh framework program (SYNCOM) to F.P. This project is supported by the Fundación Botín and by Banco Santander through its Santander Universities Global Division to F.P. F.P. and E.N. are recipients of an ICREA Acadèmia (Generalitat de Catalunya)

Osmostress-induced gene expression--a model to understand how stress-activated protein kinases (SAPKs) regulate transcription

Adaptation is essential for maximizing cell survival and for cell fitness in response to sudden changes in the environment. Several aspects of cell physiology change during adaptation. Major changes in gene expression are associated with cell exposure to environmental changes, and several aspects of mRNA biogenesis appear to be targeted by signaling pathways upon stress. Exhaustive reviews have been written regarding adaptation to stress and regulation of gene expression. In this review, using osmostress in yeast as a prototypical case study, we highlight those aspects of regulation of gene induction that are general to various environmental stresses as well as mechanistic aspects that are potentially conserved from yeast to mammals.The laboratory of F.P. and E.N. is supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2012-33503 and FEDER, BFU2014-52125-REDT and BFU2014-51672-REDC to F.P. and BFU2014-52333-P to E.N.), the Catalan Government (2014 SGR 599) and an ERC Advanced Grant (number 294294) from the EU seventh framework program (SYNCOM) to F.P. This project is supported by the Fundación Botín and by Banco Santander through its Santander Universities Global Division to F.P. F.P. and E.N. are recipients of an ICREA Acadèmia (Generalitat de Catalunya)