An essential role for p38 MAPK in cerebellar granule neuron precursor proliferation Journal Article
| Authors: | Guldal, C. G.; Ahmad, A.; Korshunov, A.; Squatrito, M.; Awan, A.; Mainwaring, L. A.; Bhatia, B.; Parathath, S. R.; Nahlé, Z.; Pfister, S.; Kenney, A. M. |
| Article Title: | An essential role for p38 MAPK in cerebellar granule neuron precursor proliferation |
| Abstract: | Development of the cerebellum occurs postnatally and is marked by a rapid proliferation of cerebellar granule neuron precursors (CGNPs). CGNPs are the cells of origin for SHH-driven medulloblastoma, the most common malignant brain tumor in children. Here, we investigated the role of ERK, JNK, and p38 mitogen-activated protein kinases in CGNP proliferation. We found high levels of p38a in proliferating CGNPs. Concomitantly, members of the p38 pathway, such as ASK1, MKK3 and ATF-2, were also elevated. Inhibition of the Shh pathway or CGNP proliferation blunts p38a levels, irrespective of Shh treatment. Strikingly, p38a levels were high in vivo in the external granule layer of the postnatal cerebellum, Shh-dependent mouse medulloblastomas and human medulloblastomas of the SHH subtype. Finally, knocking down p38a by short hairpin RNA-carrying lentiviruses as well as the pharmacologically inhibiting of its kinase activity caused a marked decrease in CGNP proliferation, underscoring its requirement for Shh-dependent proliferation in CGNPs. The inhibition of p38a also caused a decrease in Gli1 and N-myc transcript levels, consistent with reduced proliferation. These findings suggest p38 inhibition as a potential way to increase the efficacy of treatments available for malignancies associated with deregulated SHH signaling, such as basal cell carcinoma and medulloblastoma. © Springer-Verlag 2012. |
| Keywords: | cerebellum; medulloblastoma; proliferation; sonic hedgehog; neural precursor; p38 mapk |
| Journal Title: | Acta Neuropathologica |
| Volume: | 123 |
| Issue: | 4 |
| ISSN: | 0001-6322 |
| Publisher: | Springer |
| Date Published: | 2012-01-01 |
| Start Page: | 573 |
| End Page: | 586 |
| Language: | English |
| DOI: | 10.1007/s00401-012-0946-z |
| PROVIDER: | scopus |
| PUBMED: | 22302101 |
| PMCID: | PMC3775951 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 July 2012" - "CODEN: ANPTA" - "Source: Scopus" |
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