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Expression and functional validation of new p38α transcriptional targets in tumorigenesis

ABSTRACT: p38α MAP kinase plays an important tumor suppressor role, which is mediated by both its negative effect on cell proliferation and its pro-apoptotic activity. Surprisingly, most tumor suppressor mechanisms coordinated by p38α have been reported to occur at the post- translational level. This contrasts with the important role of p38α in the regulation of transcription and the profound changes in gene expression that normally occur during tumorigenesis. We have analyzed whole genome expression profiles of Ras-transformed wild- type and p38α-deficient cells and have identified 202 genes that are potentially regulated by p38α in transformed cells. Expression analysis has confirmed the regulation of these genes by p38α in tumors, and functional validation has identified several of them as likely mediators of the tumor suppressor effect of p38α on Ras-induced transformation. Interestingly, about 10% of the genes that are negatively regulated by p38α in transformed cells contribute to EGF receptor signalling. Our results suggest that inhibition of EGF receptor signalling by transcriptional targets of p38α is an important function of this signalling pathway in the context of tumor suppression.

ORGANISM(S): Mus musculus

PROVIDER: GSE26762 | GEO | 2011/11/23

SECONDARY ACCESSION(S): PRJNA136311

REPOSITORIES: GEO

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Expression and functional validation of new p38α transcriptional targets in tumorigenesis

Project description:p38α MAP kinase plays an important tumor suppressor role, which is mediated by both its negative effect on cell proliferation and its pro-apoptotic activity. Surprisingly, most tumor suppressor mechanisms coordinated by p38α have been reported to occur at the post- translational level. This contrasts with the important role of p38α in the regulation of transcription and the profound changes in gene expression that normally occur during tumorigenesis. We have analyzed whole genome expression profiles of Ras-transformed wild- type and p38α-deficient cells and have identified 202 genes that are potentially regulated by p38α in transformed cells. Expression analysis has confirmed the regulation of these genes by p38α in tumors, and functional validation has identified several of them as likely mediators of the tumor suppressor effect of p38α on Ras-induced transformation. Interestingly, about 10% of the genes that are negatively regulated by p38α in transformed cells contribute to EGF receptor signalling. Our results suggest that inhibition of EGF receptor signalling by transcriptional targets of p38α is an important function of this signalling pathway in the context of tumor suppression. We have investigated how transcriptional regulation contributes to the tumor suppressor effect of p38α, by comparing whole-genome expression profiles of wild-type (WT) and p38α- deficient (p38α-/-) mouse embryo fibroblasts (MEFs) expressing oncogenic H-RasG12V

2011-11-23 | E-GEOD-26762 | biostudies-arrayexpress

The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules

Project description:There is considerable evidence that inhibition of p38α mitogen-activated protein kinase diminishes cardiac damage during myocardial ischemia. During myocardial ischemia p38α interacts with TAB1, a scaffold protein, which promotes p38α autoactivation; active p38α (pp38α) then trans-phosphorylates TAB1. Previously, we solved the X-ray structure of the p38α-TAB1(384-412) complex. Here we further characterize the interaction by resolving the structure of the pp38α-TAB1(1-438) complex in the active state. Based on this information we created a global knock-in mouse with substitution of four residues on TAB1 (V390A, Y392A, V408G, M409A) we show are required for docking onto p38α. Whereas ablating p38α or TAB1 results in early embryonal lethality, the TAB1 KI mice are viable, develop normally and have no appreciable alteration in their lymphocyte repertoire or myocardial transcriptional profile. Nonetheless, following in vivo regional myocardial ischemia, infarction volume is significantly reduced and the trans- phosphorylation of TAB1 is disabled. Unexpectedly, the activation of myocardial p38α during ischemia is only mildly attenuated in TAB1 KI hearts, an effect most likely due to the removal of the steric hindrance to MAP2K3 binding. We conclude that it is the phosphorylation of TAB1 by pp38α during ischemia that is associated with cardiac damage. The data reveal that it is possible to selectively inhibit signalling downstream of p38α to attenuate ischemic injury. Our findings validate the p38α-TAB1 complex as a therapeutic target that may circumvent the toxicity associated with ATP-competitive inhibitors of p38α.

2018-08-27 | E-MTAB-6460 | biostudies-arrayexpress

Role of P38α in stress erythropoiesis

Project description:The P38α modulates proliferation, survival and differentiation of different kinds of celll. Here, we demonstrate that loss of P38α accelerates recovery from anemia in mice by promoting survival of erythroblasts. To identify gene expression changes in P38α+/- versus P38α-/- erythroblasts, we sorted erythroblasts from P38α+/- and P38α-/- mice during recovery from anemia and performed microarray analysis.

2018-12-21 | GSE111751 | GEO

Regulation of tumor angiogenesis and mesenchymal–endothelial transition by p38α through TGF-β and JNK signaling

Project description:The formation of new blood vessels is essential for normal development, tissue repair and tumor growth. Here we show that inhibition of the kinase p38α enhances angiogenesis in human and mouse colon tumors. Mesenchymal cells can contribute to tumor angiogenesis by regulating proliferation and migration of endothelial cells. We show that p38α negatively regulates an angiogenic program in mesenchymal stem/stromal cells (MSCs), multipotent progenitors found in perivascular locations. This program includes the acquisition of an endothelial phenotype by MSCs mediated by both TGF-β and JNK, and negatively regulated by p38α. Abrogation of p38α in mesenchymal cells increases tumorigenesis, which correlates with enhanced angiogenesis. Using genetic models, we show that p38α regulates the acquisition of an endothelial-like phenotype by mesenchymal cells in colon tumors and damage tissue. Taken together, our results indicate that p38α in mesenchymal cells restrains a TGF-β-induced angiogenesis program including their ability to transdifferentiate into endothelial cells.

2019-10-02 | GSE83810 | GEO

p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts

Project description:Hematopoietic stem cells (HSCs) and their progeny sustain lifetime hematopoiesis. Aging alters HSC function, number, and composition and increases risk of hematological malignancies, but how these changes occur in HSCs remains unclear. Signaling via p38MAPK has been proposed as a candidate mechanism underlying induction of HSC aging. Here, using genetic models of both chronological and premature aging, we describe a multimodal role for p38α, the major p38MAPK isozyme in hematopoiesis, in HSC aging. We report that p38α regulates differentiation bias and sustains transplantation capacity of HSCs in the early phase of chronological aging (from young to 1-year-old). However, p38α decreased HSC transplantation capacity in the late progression phase of chronological aging (from 1- to 2-years-old). Furthermore, co-deletion of p38α in mice deficient in Ataxia-telangiectasia mutated (Atm), a model of premature aging, exacerbated aging-related HSC phenotypes seen in Atm single mutant mice. Mechanistically, p38α makes a positive contribution to inflammation during the late phase aging, resulting in defects in 2-year-old HSCs. Overall, we propose multiple functions of p38MAPK, which both promotes and suppresses HSC aging context-dependently.

2021-03-03 | GSE168057 | GEO

Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation

Project description:The MAP kinase p38α is a central component of signalling in inflammation and the immune response, and is therefore an important drug target. Little is known about the molecular mechanism of its activation by double-phosphorylation from MAP2Ks, due to the challenge of trapping a transient and dynamic hetero-kinase complex. Here, we applied a multidisciplinary approach to generate the first structure of p38α in complex with its MAP2K MKK6 and understand the activation mechanism. Integrating cryo-EM with MD simulations and in cellulo experiments, we demonstrate a dynamic, multi-step, phosphorylation mechanism, reveal new catalytically relevant interactions, and show that MAP2K disordered N-termini determine pathway specificity. Our work captures, for the first time, a fundamental step of cell signalling: a kinase phosphorylating its downstream target kinase

2023-08-31 | PXD040499 | Pride

p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts II

2021-03-03 | GSE168085 | GEO

P38α Regulates Expression of DUX4 in Facioscapulohumeral Muscular Dystrophy

Project description:Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and specific inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity and cell death across FSHD1 and FSHD2 patient-derived lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/β inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/β inhibitors as effective therapeutics to treat FSHD at its root cause.

2020-06-26 | GSE153301 | GEO

Aberrant splicing of cdkn1a/p21 through micro-RNA mediated downregulation of JMJD6

Project description:Post-transcriptional modifications of tumor suppressors, including microRNA-mediated downregulation, are important events in tumor progression. To identify microRNAs involved in oncogenic transformation, we examined global microRNA profiles of three ras transgenic zebrafish models. Four microRNAs are upregulated in all transgenic systems. Analysis of the predicted targets shows that three of them target Jmjd6, and overexpression of Jmjd6 in ras transformed melanocytes blocks proliferation and melanoma development. We found that Jmjd6 functions to regulate splicing of the tumor suppressor cdkn1a/p21. Truncated cdkn1a/p21 transcripts, lacking the PCNA binding domain, accumulate in ras-expressing melanocytes during melanoma development. These findings implicate Jmjd6 in a novel mechanism for inactivation of a major tumor suppressor pathway in melanoma.

2017-01-01 | GSE37015 | GEO

RNA-seq analysis of HIV-1 gp120 stimulated, p38α knockout and wild-type microglia isolated from mouse brain.

Project description:Purpose: The goals of this study is to compare transcriptome profiles of microglia from different mouse genotypes using RNA-seq analysis. HIV-associated neurocognitive disorders (HAND) occur in about 50% of infected individuals. Transgenic mice expressing the soluble HIV-1 envelope glycoprotein gp120 in astroglia (HIVgp120tg) display key neuropathological features of NeuroHIV patients (Toggas et al., 1994; Maung et al., 2014; Ojeda-Juarez et al., 2020). Here we show that microglial p38α MAPK plays a crucial role in neuronal injury triggered in vivo by the viral envelope glycoprotein. Cre-expression driven by the CX3CR1 promotor in HIVgp120tg mice carrying floxed alleles of p38a MAPK results in deletion of p38α in microglia and complete protection against neuronal injury and loss. RNA-seq analysis of microglia indicates that p38α deficiency leads to upregulation of neuroprotective and downregulation of neurotoxic factors. The expression patterns of genes associated with neurotransmission differ between brains protected from neuronal injury in the presence of transgenic gp120 and non-transgenic controls, suggesting a non-toxic modulation of neurons by the viral protein and microglial p38α deficiency.

2021-10-08 | GSE185371 | GEO

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