Dataset Information

Differential regulation of mitogen- and stress-activated protein kinase-1 and -2 (MSK1 and MSK2) by CK2 following UV radiation.

ABSTRACT: Mitogen- and stress-activated protein kinases, MSK1 and the closely related isoform MSK2, are nuclear kinases that are activated following mitogen stimulation or cellular stress, including UV radiation, by the ERK1/2 and p38 MAPK signaling cascades, respectively. However, factors that differentially regulate MSK1 and MSK2 have not been well characterized. Here we report that the CK2 protein kinase, which contributes to NF-kappaB activation following UV radiation in a p38-dependent manner, physically interacts with MSK2 but not MSK1 and that CK2 inhibition specifically impairs UV-induced MSK2 kinase activation. A putative site of CK2 phosphorylation was mapped to MSK2 residue Ser(324) and when substituted to alanine (S324A) also compromised MSK2 activity. RNA interference-mediated depletion of MSK2 in human MDA-MB-231 cells, but not MSK1 depletion, resulted in impaired UV-induced phosphorylation of NF-kappaB p65 at Ser(276) in vivo, which was restored by the ectopic expression of MSK2 but not by MSK2-S324A. Furthermore, UV radiation led to the activation of NF-kappaB-responsive gene expression in MDA-MB-231 cells and induced p65 transactivation capacity that was dependent on MSK2, MSK2 residue Ser(324), and p65-Ser(276). These results suggest that MSK1 and MSK2 are differentially regulated by CK2 during the UV response and that MSK2 is the major protein kinase responsible for the UV-induced phosphorylation of p65 at Ser(276) that positively regulates NF-kappaB activity in MDA-MB-231 cells.

SUBMITTER: Jacks KA

PROVIDER: S-EPMC2804324 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Differential regulation of mitogen- and stress-activated protein kinase-1 and -2 (MSK1 and MSK2) by CK2 following UV radiation.

Jacks Kellie A KA Koch C Anne CA

The Journal of biological chemistry 20091120 3

Mitogen- and stress-activated protein kinases, MSK1 and the closely related isoform MSK2, are nuclear kinases that are activated following mitogen stimulation or cellular stress, including UV radiation, by the ERK1/2 and p38 MAPK signaling cascades, respectively. However, factors that differentially regulate MSK1 and MSK2 have not been well characterized. Here we report that the CK2 protein kinase, which contributes to NF-kappaB activation following UV radiation in a p38-dependent manner, physic ...[more]

PMID: 19933278

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Project description:Analysis of alterations in the hippocampus transcriptome caused by deletion of Mitogen Stress activated Kinase 1 (MSK1). MAPK signaling has been implicated in a wide range of neuronal processes, including development, plasticity and viability. One of the principal downstream targets of both the ERK/MAPK pathway and the p38 MAPK pathway is Mitogen Stress activated Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized a MSK1 null mouse line, cell viability assays and array-based profiling approaches. Here we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus (SE) drives acute induction of MSK1 activation. In response to the SE paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of NMDA-evoked excitotoxicity relative to WT neurons, as assessed using the LDH assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that with MSK1 deletion a total of 115 genes showed significant changes (> 1.25-fold) in expression. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults. MAPK signaling has been implicated in a wide range of neuronal processes, including development, plasticity and viability. One of the principal downstream targets of both the ERK/MAPK pathway and the p38 MAPK pathway is Mitogen Stress activated Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized a MSK1 null mouse line, cell viability assays and array-based profiling approaches. Here we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus (SE) drives acute induction of MSK1 activation. In response to the SE paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of NMDA-evoked excitotoxicity relative to WT neurons, as assessed using the LDH assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that with MSK1 deletion a total of 115 genes showed significant changes (> 1.25-fold) in expression. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults.

Project description:Radiation biodosimetry based on transcriptomic analysis of peripheral blood is a valuable tool to detect radiation exposure after a radiological/nuclear event and obtain useful biological information that could predict tissue and organismal injury. However, confounding factors, including inflammation, can potentially obscure the predictive power of the method. The mitogen-activated protein kinase (MAPK) p38 is normally regulated by the MAP3K-MAP2K pathway in mammalian cells. Members of the p38 MAPK family respond to pro-inflammatory signals and environmental stresses. However, in T cells there is an alternative pathway for p38MAPK activation. This pathway has been shown to play an important role in antigen-receptor-activated T cells and participate in immune and inflammatory responses. Radiation is known to induce a pro-inflammatory response. To examine the role of p38MAPK in response to radiation, we used two mouse models expressing either a p38αMAPK dominant negative (DN) mutation that would be expected to globally suppress p38MAPK signaling or a double knock-in (DKI) mutant, which would be expected to inhibit specifically T cell receptor activation. We exposed wild-type and p38MAPK mutant mice to 7 Gy x-rays and 24 h later we isolated whole blood and performed genome microarray and gene ontology analysis. Comparison between the two mutants (DN, DKI) suggest that the alternative p38MAPK pathway may have wider functions in the response to radiation exposure beyond its well established role as a downstream effector of activated T-cell receptor. Among the differentially enriched pathways, irradiation leads to a significant overrepresentation of pathways associated with morbidity and mortality as well as organismal cell death. In contrast, these pathways were significantly underrepresented in p38MAPKDN and p38MAPKDKI mutant mice, implying that p38MAPK suppression protects mice from the deleterious effects of radiation. Furthermore, radiation exposure resulted in an enrichment of a small number of phagocytosis-related pathways; however, considerably more phagocytosis-related pathways were overrepresented in the p38MAPK mutant mice, implying that p38MAPK signaling, normally, restricts phagocytosis of apoptotic cells after radiation and may, thus, contribute to persistent inflammation. Finally, despite the significant changes in gene expression, we were still able to identify a panel of genes that could accurately distinguish between irradiated and control mice, irrespective of p38MAPK status.

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Dataset Information

Differential regulation of mitogen- and stress-activated protein kinase-1 and -2 (MSK1 and MSK2) by CK2 following UV radiation.

Publications

Differential regulation of mitogen- and stress-activated protein kinase-1 and -2 (MSK1 and MSK2) by CK2 following UV radiation.

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