p27Kip1, a double-edged sword in Shh-mediated medulloblastoma: Tumor accelerator and suppressor Journal Article
| Authors: | Bhatia, B.; Malik, A.; Fernandez-L, A.; Kenney, A. M. |
| Article Title: | p27Kip1, a double-edged sword in Shh-mediated medulloblastoma: Tumor accelerator and suppressor |
| Abstract: | Medulloblastoma, a brain tumor arising in the cerebellum, is the most common solid childhood malignancy. The current standard of care for medulloblastoma leaves survivors with life-long side effects. Gaining insight into mechanisms regulating transformation of medulloblastoma cells-of-origin may lead to development of better treatments for these tumors. Cerebellar granule neuron precursors (CGNPs) are proposed cells-of-origin for certain classes of medulloblastoma, specifically those marked by aberrant Sonic hedgehog (Shh) signaling pathway activation. CGNPs require signaling by Shh for proliferation during brain development. In mitogen-stimulated cells, nuclear localized cyclin dependent kinase (cdk) inhibitor p27 (Kip1) functions as a checkpoint control at the G1- to S-phase transition by inhibiting cdk2. Recent studies have suggested cytoplasmically localized p27Kip1 acquires oncogenic functions. Here, we show that p27Kip1 is cytoplasmically localized in CGNPs and mouse Shh-mediated medulloblastomas. Transgenic mice bearing an activating mutation in the Shh pathway and lacking one or both p27Kip1 alleles have accelerated tumor incidence compared to mice bearing both p27 Kip1 alleles. Interestingly, mice heterozygous for p27Kip1 have decreased survival latency compared to p27Kip1-null animals. Our data indicate that this may reflect the requirement for at least one copy of p27Kip1 for recruiting cyclin D/cdk4/6 to promote cell cycle progression yet insufficient expression in the heterozygous or null state to inhibit cyclin E/cdk2. Finally, we find that mis-localized p27Kip1 may play a positive role in motility in medulloblastoma cells. Together, our data indicate that the dosage of p27Kip1 plays a role in cell cycle progression and tumor suppression in Shh-mediated medulloblastoma expansion. © 2010 Landes Bioscience. |
| Keywords: | signal transduction; genetics; nonhuman; protein localization; animal cell; mouse; animal; metabolism; animals; mice; cerebellum; cells, cultured; mus; cell cycle; cell cycle progression; cell cycle s phase; sonic hedgehog protein; hedgehog proteins; transgenic mouse; animalia; mus musculus; mice, transgenic; stem cell; cell culture; brain development; cyclin dependent kinase inhibitor 1b; medulloblastoma; cyclin-dependent kinase inhibitor p27; tumor suppressor proteins; newborn; cellular distribution; tumor; tumor suppressor protein; sonic hedgehog; cerebellar neoplasms; erinaceidae; cell cycle g1 phase; shh protein, mouse; g1 phase; s phase; motility; cyclin e; cyclin dependent kinase 4; cyclin-dependent kinase 4; cyclin d; mitogenic agent; cyclin dependent kinase 6; cyclin dependent kinase 2; kip1; p27; rhoa; cdk2 protein, mouse; cdk4 protein, mouse; cdk6 protein, mouse; cdkn1b protein, mouse; cerebellum tumor; cyclin-dependent kinase 2; cyclin-dependent kinase 6 |
| Journal Title: | Cell Cycle |
| Volume: | 9 |
| Issue: | 21 |
| ISSN: | 1538-4101 |
| Publisher: | Taylor & Francis Inc. |
| Date Published: | 2010-11-01 |
| Start Page: | 4307 |
| End Page: | 4314 |
| Language: | English |
| DOI: | 10.4161/cc.9.21.13441 |
| PUBMED: | 21051932 |
| PROVIDER: | scopus |
| PMCID: | PMC3055184 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "Source: Scopus" |
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