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Induction of oxidative metabolism by the p38α/MK2 pathway.

ABSTRACT: Adequate responses to environmental stresses are essential for cell survival. The regulation of cellular energetics that involves mitochondrial energy production and oxidative stress is central in the process of stress adaptation and response. The p38α signalling pathway plays a key role in the response to stress stimuli by orchestrating multiple cellular processes. However, prolonged activation of the p38α pathway results in impaired cell proliferation and can lead to cell death. Here we use a system to specifically activate p38α signalling and show that sustained activation of this pathway suffices to induce important metabolic changes, including high dependence on glucose for cell survival, increased consumption of glutamine, enhanced respiration rate and elevated production of mitochondrial reactive oxygen species (ROS). Moreover, we provide evidence that increased production of mitochondrial superoxide as a consequence of elevated mitochondria activity, contributes to the p38α reduced cell survival triggered by sustained p38α activation. We also show that the p38α-activated kinase MAPKAPK2 (MK2) plays an important role orchestrating the observed metabolic changes. Our results illustrate a new function of p38α signalling in the regulation of cellular metabolism, which may lead to cell death upon persistent activation of the pathway.

SUBMITTER: Trempolec N

PROVIDER: S-EPMC5595987 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Positive feedback between ROS and cis-axis of PIASxα/p38α-SUMOylation/MK2 facilitates gastric cancer metastasis.

Project description:MAPK/p38 is an important mammalian signaling cascade that responds to a variety of intracellular or extracellular stimuli, such as reactive oxygen species (ROS), and participates in numerous physiological and pathological processes. However, the biological function of p38 in different tumors, and even at different stages of the same tumor, remains elusive. To further understand the regulatory mechanism of p38 and oxidative stress in the occurrence and development of gastric cancer, we report SUMOylation as a novel post-translational modification occurring on lysine 152 of MAPK14/p38α through immunoprecipitation and series of pull-down assays in vitro and in vivo. Importantly, we determine that p38α-SUMOylation functions as an authentic sensor and accelerator of reactive oxygen species generation via interaction with and activation of MK2 in the nucleus, and the ROS accumulation, in turn, promotes the SUMOylation of p38α by stabilizing the PIASxα protein. This precise regulatory mechanism is exploited by gastric cancer cells to create an internal environment for survival and, ultimately, metastasis. This study reveals novel insights into p38α-SUMOylation and its association with the intracellular oxidative stress response, which is closely related to the processes of gastric cancer. Furthermore, the PIASxα/p38α-SUMOylation/MK2 cis-axis may serve as a desirable therapeutic target in gastric cancer as targeting PIASxα, MK2, or a specific peptide region of p38α may reconcile the aberrant oxidative stress response in gastric cancer cells.

| S-EPMC8536665 | biostudies-literature

NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism.

Project description:NADPH donates high energy electrons for antioxidant defense and reductive biosynthesis. Cytosolic NADP is recycled to NADPH by the oxidative pentose phosphate pathway (oxPPP), malic enzyme 1 (ME1) and isocitrate dehydrogenase 1 (IDH1). Here we show that any one of these routes can support cell growth, but the oxPPP is uniquely required to maintain a normal NADPH/NADP ratio, mammalian dihydrofolate reductase (DHFR) activity and folate metabolism. These findings are based on CRISPR deletions of glucose-6-phosphate dehydrogenase (G6PD, the committed oxPPP enzyme), ME1, IDH1, and combinations thereof in HCT116 colon cancer cells. Loss of G6PD results in high NADP, which induces compensatory increases in ME1 and IDH1 flux. But the high NADP inhibits dihydrofolate reductase (DHFR), resulting in impaired folate-mediated biosynthesis, which is reversed by recombinant expression of E. coli DHFR. Across different cancer cell lines, G6PD deletion produced consistent changes in folate-related metabolites, suggesting a general requirement for the oxPPP to support folate metabolism.

| S-EPMC6489125 | biostudies-literature

p38α deficiency restrains liver regeneration after partial hepatectomy triggering oxidative stress and liver injury.

Project description:p38α MAPK negatively regulates the G1/S and G2/M cell cycle transitions. However, liver-specific p38α deficiency impairs cytokinesis and reduces hepatocyte proliferation during cirrhosis and aging in mice. In this work, we have studied how p38α down-regulation affects hepatocyte proliferation after partial hepatectomy, focusing on mitotic progression, cytokinesis and oxidative stress. We found that p38α deficiency triggered up-regulation of cyclins A1, B1, B2, and D1 under basal conditions and after hepatectomy. Moreover, p38α-deficient hepatocytes showed enhanced binucleation and increased levels of phospho-histone H3 but impaired phosphorylation of MNK1 after hepatectomy. The recovery of liver mass was transiently delayed in mice with p38α-deficient hepatocytes vs wild type mice. We also found that p38α deficiency caused glutathione oxidation in the liver, increased plasma aminotransferases and lactate dehydrogenase activities, and decreased plasma protein levels after hepatectomy. Interestingly, p38α silencing in isolated hepatocytes markedly decreased phospho-MNK1 levels, and silencing of either p38α or Mnk1 enhanced binucleation of hepatocytes in culture. In conclusion, p38α deficiency impairs mitotic progression in hepatocytes and restrains the recovery of liver mass after partial hepatectomy. Our results also indicate that p38α regulates cytokinesis by activating MNK1 and redox modulation.

| S-EPMC6405944 | biostudies-literature

p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage.

Project description:Ultraviolet (UV) light radiation induces the formation of bulky photoproducts in the DNA that globally affect transcription and splicing. However, the signaling pathways and mechanisms that link UV-light-induced DNA damage to changes in RNA metabolism remain poorly understood. Here we employ quantitative phosphoproteomics and protein kinase inhibition to provide a systems view on protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on the canonical DNA damage signaling by ATM/ATR and the p38 MAP kinase pathway. We identify RNA-binding proteins as primary substrates and 14-3-3 as direct readers of p38-MK2-dependent phosphorylation induced by UV light. Mechanistically, we show that MK2 phosphorylates the RNA-binding subunit of the NELF complex NELFE on Serine 115. NELFE phosphorylation promotes the recruitment of 14-3-3 and rapid dissociation of the NELF complex from chromatin, which is accompanied by RNA polymerase II elongation.

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Characterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway.

Project description:p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38α signaling has been linked to several diseases including inflammation, immune disorders and cancer, suggesting that targeting p38α could be therapeutically beneficial. Over the last two decades, numerous p38α inhibitors have been developed, which showed promising effects in pre-clinical studies but results from clinical trials have been disappointing, fueling the interest in the generation of alternative mechanisms of p38α modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38α inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38α autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38α can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathway.

| S-EPMC10261013 | biostudies-literature

p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication.

Project description:The DNA damage response activates several pathways that stall the cell cycle and allow DNA repair. These consist of the well-characterized ATR (Ataxia telangiectasia and Rad-3 related)/CHK1 and ATM (Ataxia telangiectasia mutated)/CHK2 pathways in addition to a newly identified ATM/ATR/p38MAPK/MK2 checkpoint. Crucial to maintaining the integrity of the genome is the S-phase checkpoint that functions to prevent DNA replication until damaged DNA is repaired. Inappropriate expression of the proto-oncogene c-Myc is known to cause DNA damage. One mechanism by which c-Myc induces DNA damage is through binding directly to components of the prereplicative complex thereby promoting DNA synthesis, resulting in replication-associated DNA damage and checkpoint activation due to inappropriate origin firing. Here we show that following etoposide-induced DNA damage translation of c-Myc is repressed by miR-34c via a highly conserved target-site within the 3(') UTR. While miR-34c is induced by p53 following DNA damage, we show that in cells lacking p53 this is achieved by an alternative pathway which involves p38 MAPK signalling to MK2. The data presented here suggest that a major physiological target of miR-34c is c-Myc. Inhibition of miR-34c activity prevents S-phase arrest in response to DNA damage leading to increased DNA synthesis, DNA damage, and checkpoint activation in addition to that induced by etoposide alone, which are all reversed by subsequent c-Myc depletion. These data demonstrate that miR-34c is a critical regulator of the c-Myc expression following DNA damage acting downstream of p38 MAPK/MK2 and suggest that miR-34c serves to remove c-Myc to prevent inappropriate replication which may otherwise lead to genomic instability.

| S-EPMC2851793 | biostudies-literature

p38-MK2 regulate RNA metabolism after UV light-induced DNA damage

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-11-24 | GSE90556 | GEO

p38-MK2 regulate RNA metabolism after UV light-induced DNA damage

Project description:Ultraviolet (UV) light induces the formation of bulky UV photoproducts in the genome that interfere with DNA replication and transcription. It is well-established how human cells repair UV light-induced DNA lesions, however the signaling pathways and mechanisms that regulate transcription after exposure to UV light are poorly understood. Here, we provide a systematic view on dynamic protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on canonical DNA damage kinases and the p38 MAP kinase pathway. Notably, we demonstrate that p38 and its downstream effector kinase MK2 are responsible for one quarter of protein phosphorylation induced by UV light. We identify RNA binding proteins as primary targets and 14-3-3 family proteins as direct readers of UV light-induced, p38-MK2-dependent phosphorylation. Importantly, we demonstrate that UV light triggers rapid and dynamic phosphorylation of the negative elongation factor (NELF) complex subunit NELFE on serine 115 that mediates its binding to 14-3-3. NELFE interaction with 14-3-3 stabilizes NELFE and RNA pol II interaction on the chromatin and inhibits transcriptional elongation, thereby promoting cell survival after UV light.

2019-11-24 | GSE90555 | GEO

p38-MK2 regulate RNA metabolism after UV light-induced DNA damage

2019-11-24 | GSE90554 | GEO

The p38/MK2/Hsp25 pathway is required for BMP-2-induced cell migration.

Project description:BackgroundBone morphogenetic proteins (BMPs) have been shown to participate in the patterning and specification of several tissues and organs during development and to regulate cell growth, differentiation and migration in different cell types. BMP-mediated cell migration requires activation of the small GTPase Cdc42 and LIMK1 activities. In our earlier report we showed that activation of LIMK1 also requires the activation of PAKs through Cdc42 and PI3K. However, the requirement of additional signaling is not clearly known.Methodology/principal findingsActivation of p38 MAPK has been shown to be relevant for a number of BMP-2's physiological effects. We report here that BMP-2 regulation of cell migration and actin cytoskeleton remodelling are dependent on p38 activity. BMP-2 treatment of mesenchymal cells results in activation of the p38/MK2/Hsp25 signaling pathway downstream from the BMP receptors. Moreover, chemical inhibition of p38 signaling or genetic ablation of either p38? or MK2 blocks the ability to activate the downstream effectors of the pathway and abolishes BMP-2-induction of cell migration. These signaling effects on p38/MK2/Hsp25 do not require the activity of either Cdc42 or PAK, whereas p38/MK2 activities do not significantly modify the BMP-2-dependent activation of LIMK1, measured by either kinase activity or with an antibody raised against phospho-threonine 508 at its activation loop. Finally, phosphorylated Hsp25 colocalizes with the BMP receptor complexes in lamellipodia and overexpression of a phosphorylation mutant form of Hsp25 is able to abolish the migration of cells in response to BMP-2.ConclusionsThese results indicate that Cdc42/PAK/LIMK1 and p38/MK2/Hsp25 pathways, acting in parallel and modulating specific actin regulatory proteins, play a critical role in integrating responses during BMP-induced actin reorganization and cell migration.

| S-EPMC3030584 | biostudies-literature

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