p27(Kip1), a double-edged sword in Shh-mediated medulloblastoma: Tumor accelerator and suppressor.
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 p27(Kip1) acquires oncogenic functions. Here, we show that p27(Kip1) 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 p27(Kip1) alleles have accelerated tumor incidence compared to mice bearing both p27(Kip1) alleles. Interestingly, mice heterozygous for p27(Kip1) have decreased survival latency compared to p27(Kip1)-null animals. our data indicate that this may reflect the requirement for at least one copy of p27(Kip1) 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 p27(Kip1) may play a positive role in motility in medulloblastoma cells. Together, our data indicate that the dosage of p27(Kip1) plays a role in cell cycle progression and tumor suppression in Shh-mediated medulloblastoma expansion.
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Bobby
B
Bhatia
Arfa
A
Malik
Africa
A
Fernandez-L
Anna Marie
AM
Kenney
D000818:Animals; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000378:metabolism*; D056741:Cyclin D / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase; D053823:Hedgehog Proteins / Q000378:metabolism*; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016196:S Phase; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C493961:Cdkn1b protein, mouse; D056741:Cyclin D; D019927:Cyclin E; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6