Diversity and versatility of p38 kinase signalling in health and disease

Cánovas, Begoña; Nebreda, Angel R.

doi:10.1038/s41580-020-00322-w

Cited by 321 publications

(328 citation statements)

References 269 publications

(329 reference statements)

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“…In another study, Losmapimod was shown to disrupt SARS-CoV-2 replication in a model of primary alveolar epithelial cells, suggesting that p38 is a potential target for COVID-19 treatment [58]. In fact, Losmapimod is currently being tested in a clinical trial with COVID-19 affected patients [40].…”

Section: Discussionmentioning

confidence: 99%

“…PROTACs function by recognizing a specific protein substrate and recruiting an E3 ubiquitin ligase that promotes the polyubiquitination of the protein of interest and its subsequent degradation in the proteasome [37,38]. The p38 MAPK family includes four isoforms: p38⍺, p38β, p38γ and p38δ [39,40]. While p38⍺ and p38β are ubiquitously expressed in most tissues, p38γ and p38δ have a restricted expression [40].…”

Section: Knockdown Of P38⍺ and P38β Isoforms In Hdfs With The Protacs Molecule Nr-7h Reduces Mayv Replicationmentioning

confidence: 99%

“…The p38 MAPK family includes four isoforms: p38⍺, p38β, p38γ and p38δ [39,40]. While p38⍺ and p38β are ubiquitously expressed in most tissues, p38γ and p38δ have a restricted expression [40]. Recently, it has been reported that nanomolar concentrations of the PROTACs compound NR-7h are able to induce the specific degradation of p38⍺ and p38β isoforms, thereby, blocking stress-and cytokine-induced downstream signaling by p38 [41].…”

Section: Knockdown Of P38⍺ and P38β Isoforms In Hdfs With The Protacs Molecule Nr-7h Reduces Mayv Replicationmentioning

confidence: 99%

“…Since p38 has been implicated in different pathologies, including inflammatory diseases, neurological disorders and cancer, pharmaceutical companies have developed diverse small inhibitory molecules targeting this kinase [39,40,42,43]. Among them, Losmapimod is a highly selective and potent inhibitor against p38⍺ and p38β isoforms that has been evaluated in different clinical trials and shown to be well tolerated and safe [44][45][46].…”

Section: Losmapimod a P38 Inhibitor Under Clinical Evaluation Decreases Mayv Replication In Hdfsmentioning

confidence: 99%

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Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Sugasti¹,

Llamas-González²,

Campos³

et al. 2021

Preprint

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Mayaro virus (MAYV) hijacks the host´s cell machinery to effectively replicate. The mitogen-activated protein kinases (MAPKs) p38, JNK and ERK1/2 have emerged as crucial cellular factors implicated in different stages of the viral cycle. However, whether MAYV uses these MAPKs to competently replicate has not yet been determined. The aim of this study was to evaluate the impact of MAPKs inhibition on MAYV replication using primary human dermal fibroblasts (HDFs) and HeLa cells. Viral yields in supernatants from MAYV-infected cells treated or untreated with inhibitors SB203580, SP600125, U0126 or Losmapimod were quantified using plaque assay. Also, viral protein expression was analyzed using immunoblot and immunofluorescence. Knockdown of p38⍺/p38β isoforms was performed in HDFs using the PROTACs molecule NR-7h. Our data demonstrated that HDFs are highly susceptible to MAYV infection. SB203580, a p38 inhibitor, reduced MAYV replication in a dose-dependent manner in both HDFs and HeLa cells. Additionally, SB203580 significantly decreased viral E1 protein expression. Similarly, knockdown or inhibition of p38⍺/p38β isoforms with NR-7h or Losmapimod, respectively, affected MAYV replication in a dose-dependent manner. Collectively, these findings suggest that p38 could play an important role in MAYV replication and could serve as a therapeutic target to control MAYV infection.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Knockdown Of P38⍺ and P38β Isoforms In Hdfs With The Protacs Molecule Nr-7h Reduces Mayv Replicationmentioning

confidence: 99%

Section: Knockdown Of P38⍺ and P38β Isoforms In Hdfs With The Protacs Molecule Nr-7h Reduces Mayv Replicationmentioning

confidence: 99%

Section: Losmapimod a P38 Inhibitor Under Clinical Evaluation Decreases Mayv Replication In Hdfsmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Sugasti¹,

Llamas-González²,

Campos³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Notably, the systemic or local administration of MMI-0100 (a cell-permeable synthetic peptide composed of 22 amino acid residues) to mice reverses established lung fibrosis by BLM, suggesting its clinical application [ 95 ]. Although MK2 is theoretically a downstream substrate of all p38 isoforms, the best characterized member of the family regulating MK2 is p38α [ 96 ]. Furthermore, among the p38 family members, p38α is shown to most potently regulate the cell migration where MK2 activation is required [ 97 ].…”

Section: Involvement Of P38 In the Pathogenesis Of Pulmonary Fibrosismentioning

confidence: 99%

Pathophysiological Roles of Stress-Activated Protein Kinases in Pulmonary Fibrosis

Kasuya

Kim

Hatano

et al. 2021

IJMS

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Idiopathic pulmonary fibrosis (IPF) is one of the most symptomatic progressive fibrotic lung diseases, in which patients have an extremely poor prognosis. Therefore, understanding the precise molecular mechanisms underlying pulmonary fibrosis is necessary for the development of new therapeutic options. Stress-activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) are ubiquitously expressed in various types of cells and activated in response to cellular environmental stresses, including inflammatory and apoptotic stimuli. Type II alveolar epithelial cells, fibroblasts, and macrophages are known to participate in the progression of pulmonary fibrosis. SAPKs can control fibrogenesis by regulating the cellular processes and molecular functions in various types of lung cells (including cells of the epithelium, interstitial connective tissue, blood vessels, and hematopoietic and lymphoid tissue), all aspects of which remain to be elucidated. We recently reported that the stepwise elevation of intrinsic p38 signaling in the lungs is correlated with a worsening severity of bleomycin-induced fibrosis, indicating an importance of this pathway in the progression of pulmonary fibrosis. In addition, a transcriptome analysis of RNA-sequencing data from this unique model demonstrated that several lines of mechanisms are involved in the pathogenesis of pulmonary fibrosis, which provides a basis for further studies. Here, we review the accumulating evidence for the spatial and temporal roles of SAPKs in pulmonary fibrosis.

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Thromboxane A₂ Modulates de novo Synthesis of Adrenal Corticosterone in Mice via p38/14‐3‐3γ/StAR Signaling

Yan,

Wang,

Wang

et al. 2024

Advanced Science

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Prostanoids are endogenous lipid bioactive mediators that play essential roles in physiological processes such as glucocorticoid secretion. Here, it is found that the thromboxane (Tx)A2 receptor (TP) is highly expressed in the adrenal cortex of mice. Both global and adrenocortical‐specific deletion of the TP receptor lead to increased adiposity in mice by elevating corticosterone synthesis. Mechanistically, the TP receptor deletion increases the phosphorylation of steroidogenic acute regulatory protein (StAR) and corticosterone synthesis in adrenal cortical cells by suppressing p‐p38‐mediated phosphorylation of 14‐3‐3γ adapter protein at S71. The activation of the p38 in the adrenal cortical cells by forced expression of the MKK6EE gene attenuates hypercortisolism in TP‐deficient mice. These observations suggest that the TxA2/TP signaling regulates adrenal corticosterone homeostasis independent of the hypothalamic–pituitary–adrenal axis and the TP receptor may serve as a promising therapeutic target for hypercortisolism.

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Diversity and versatility of p38 kinase signalling in health and disease

Cited by 321 publications

References 269 publications

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Pathophysiological Roles of Stress-Activated Protein Kinases in Pulmonary Fibrosis

Thromboxane A₂ Modulates de novo Synthesis of Adrenal Corticosterone in Mice via p38/14‐3‐3γ/StAR Signaling

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Diversity and versatility of p38 kinase signalling in health and disease

Cited by 321 publications

References 269 publications

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Pathophysiological Roles of Stress-Activated Protein Kinases in Pulmonary Fibrosis

Thromboxane A2 Modulates de novo Synthesis of Adrenal Corticosterone in Mice via p38/14‐3‐3γ/StAR Signaling

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Product

Resources

About

Thromboxane A₂ Modulates de novo Synthesis of Adrenal Corticosterone in Mice via p38/14‐3‐3γ/StAR Signaling