An essential role for p38 MAPK in cerebellar granule neuron precursor proliferation

Guldal, Cemile G.; Ahmad, Adiba; Korshunov, Andrey; Squatrito, Massimo; Awan, Aashir; Mainwaring, Lori; Bhatia, Bipin; Parathath, Susana R.; Nahlé, Zaher; Pfister, Stefan M.; Kenney, Anna Marie

doi:10.1007/s00401-012-0946-z

Cited by 19 publications

(16 citation statements)

References 67 publications

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“…For instance, CGN precursors induced to proliferate with the morphogen sonic hedgehog (shh) have elevated p38␣ protein levels and display heightened p38␣ activity (49). The increase of p38␣ protein upon shh exposure was a posttranscriptional event, since p38␣ mRNA levels were unchanged (49). Similar to our results and in accordance with a role for shh in proliferation control, elevated p38␣ hances Mnk1-dependent phosphorylation of eIF4E(Ser209).…”

Section: Discussionsupporting

confidence: 86%

“…This indicates that these miRNAs play a role in posttranscriptional p38␣ regulation in the adult brain. For instance, CGN precursors induced to proliferate with the morphogen sonic hedgehog (shh) have elevated p38␣ protein levels and display heightened p38␣ activity (49). The increase of p38␣ protein upon shh exposure was a posttranscriptional event, since p38␣ mRNA levels were unchanged (49).…”

Section: Discussionmentioning

confidence: 99%

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p38α Mitogen-Activated Protein Kinase Depletion and Repression of Signal Transduction to Translation Machinery by miR-124 and -128 in Neurons

Lawson

Dobrikova

Shveygert

et al. 2013

Molecular and Cellular Biology

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The p38␣ to p38␦ mitogen-activated protein kinases (MAPKs) are central regulatory nodes coordinating acute stress and inflammatory responses. Their activation leads to rapid adjustment of protein synthesis, for instance translational induction of proinflammatory cytokines. The only known direct link of p38 to translation machinery is the MAPK signal-integrating kinase Mnk. Only p38␣ and p38␤ transcripts are ubiquitously expressed. These mRNAs encode highly conserved proteins that equally phosphorylate recombinant Mnk1 in vitro. We discovered that expression of the p38␣ protein, but not the p38␤ isoform, is suppressed in the brain. This is due to p38␣ depletion by two neuron-selective microRNAs (miRNAs), miR-124 and -128. Suppression of p38␣ protein was reversed by miR-124/-128 antisense oligonucleotides in primary explant neuronal cultures. Targeted p38␣ depletion reduced Mnk1 activation, which cannot be compensated by p38␤. Our research shows that p38␣ alone controls acute stress and cytokine signaling from p38 MAPK to translation machinery. This regulatory axis is greatly diminished in neurons, which may insulate brain physiology and function from p38␣-Mnk1-mediated signaling.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

p38α Mitogen-Activated Protein Kinase Depletion and Repression of Signal Transduction to Translation Machinery by miR-124 and -128 in Neurons

Lawson

Dobrikova

Shveygert

et al. 2013

Molecular and Cellular Biology

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“…) without affecting proliferation of these cells (Guldal et al . ). It will be important to establish in the future how OGR1 activation links to ERK phosphorylation, if TPRC4 is a target for the ERK signalling pathway, and what (other) effects OGR1‐mediated ERK activation has on granule precursor cells and their transformed counterparts.…”

Section: Discussionmentioning

confidence: 97%

Functional expression of calcium‐permeable canonical transient receptor potential 4‐containing channels promotes migration of medulloblastoma cells

Wei

Huang

Lin

et al. 2017

The Journal of Physiology

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Key points The proton sensing ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) promotes expression of the canonical transient receptor potential channel subunit TRPC4 in normal and transformed cerebellar granule precursor (DAOY) cells.OGR1 and TRPC4 are prominently expressed in healthy cerebellar tissue throughout postnatal development and in primary cerebellar medulloblastoma tissues.Activation of TRPC4‐containing channels in DAOY cells, but not non‐transformed granule precursor cells, results in prominent increases in [Ca2+]i and promotes cell motility in wound healing and transwell migration assays.Medulloblastoma cells not arising from granule precursor cells show neither prominent rises in [Ca2+]i nor enhanced motility in response to TRPC4 activation unless they overexpressTRPC4.Our results suggest that OGR1 enhances expression of TRPC4‐containing channels that contribute to enhanced invasion and metastasis of granule precursor‐derived human medulloblastoma. AbstractAberrant intracellular Ca2+ signalling contributes to the formation and progression of a range of distinct pathologies including cancers. Rises in intracellular Ca2+ concentration occur in response to Ca2+ influx through plasma membrane channels and Ca2+ release from intracellular Ca2+ stores, which can be mobilized in response to activation of cell surface receptors. Ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) is a proton‐sensing Gq‐coupled receptor that is most highly expressed in cerebellum. Medulloblastoma (MB) is the most common paediatric brain tumour that arises from cerebellar precursor cells. We found that nine distinct human MB samples all expressed OGR1. In both normal granule cells and the transformed human cerebellar granule cell line DAOY, OGR1 promoted expression of the proton‐potentiated member of the canonical transient receptor potential (TRPC) channel family, TRPC4. Consistent with a role for TRPC4 in MB, we found that all MB samples also expressed TRPC4. In DAOY cells, activation of TRPC4‐containing channels resulted in large Ca2+ influx and enhanced migration, while in normal cerebellar granule (precursor) cells and MB cells not derived from granule precursors, only small levels of Ca2+ influx and no enhanced migration were observed. Our results suggest that OGR1‐dependent increases in TRPC4 expression may favour formation of highly Ca2+‐permeable TRPC4‐containing channels that promote transformed granule cell migration. Increased motility of cancer cells is a prerequisite for cancer invasion and metastasis, and our findings may point towards a key role for TRPC4 in progression of certain types of MB.

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“…EAG2 knockdown induced a very robust (11.83-fold) increase in the phospho-p38 level. It is possible that this level of p38 MAPK pathway activation exceeded that of the CGNPs treated with Shh (Guldal et al 2012) so that it prevented cell proliferation. It is also possible that the p38 MAPK pathway is protective for CGNP growth by preventing excessive oxidative and genotoxic stress associated with rapid cell division.…”

Section: Discussionmentioning

confidence: 99%

“…However, in some circumstances, p38 MAPK pathway activation has been found to promote cell proliferation (Hegle et al 2006;Ayllon and O'Connor 2007), as is the case for CGNPs (Guldal et al 2012). In our study, the p38 MAPK inhibitor SB203580 had minimal effects on Vandy-MB-11 cell growth but profoundly reversed the growth defects of EAG2-depleted cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

et al. 2012

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Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.

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An essential role for p38 MAPK in cerebellar granule neuron precursor proliferation

Cited by 19 publications

References 67 publications

p38α Mitogen-Activated Protein Kinase Depletion and Repression of Signal Transduction to Translation Machinery by miR-124 and -128 in Neurons

p38α Mitogen-Activated Protein Kinase Depletion and Repression of Signal Transduction to Translation Machinery by miR-124 and -128 in Neurons

Functional expression of calcium‐permeable canonical transient receptor potential 4‐containing channels promotes migration of medulloblastoma cells

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

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