Tuberous sclerosis complex suppression in cerebellar development and medulloblastoma: Separate regulation of mammalian target of rapamycin activity and p27-Kip1 localization Journal Article


Authors: Bhatia, B.; Northcott, P. A.; Hambardzumyan, D.; Govindarajan, B.; Brat, D. J.; Arbiser, J. L.; Holland, E. C.; Taylor, M. D.; Kenney, A. M.
Article Title: Tuberous sclerosis complex suppression in cerebellar development and medulloblastoma: Separate regulation of mammalian target of rapamycin activity and p27-Kip1 localization
Abstract: During development, proliferation of cerebellar granule neuron precursors (CGNP), candidate cells-of-origin for the pediatric brain tumor medulloblastoma, requires signaling by Sonic hedgehog (Shh) and insulin-like growth factor (IGF), the pathways of which are also implicated in medulloblastoma. One of the consequences of IGF signaling is inactivation of the mammalian target of rapamycin (mTOR)-suppressing tuberous sclerosis complex (TSC), comprised of TSC1 and TSC2, leading to increased mRNA translation. We show that mice, in which TSC function is impaired, display increased mTOR pathway activation, enhanced CGNP proliferation, glycogen synthase kinase-3α/β (GSK-3α/β) inactivation, and cytoplasmic localization of the cyclin-dependent kinase inhibitor p27<sup>Kip1</sup>, which has been proposed to cause its inactivation or gain of oncogenic functions. We observed the same characteristics in wild-type primary cultures of CGNPs in which TSC1 and/or TSC2 were knocked down, and in mouse medulloblastomas induced by ectopic Shh pathway activation. Moreover, Shh-induced mouse medulloblastomas manifested Akt-mediated TSC2 inactivation, and the mutant TSC2 allele synergized with aberrant Shh signaling to increase medulloblastoma incidence in mice. Driving exogenous TSC2 expression in Shh-induced medulloblastoma cells corrected p27<sup>Kip1</sup> localization and reduced proliferation. GSK-3α/β inactivation in the tumors in vivo and in primary CGNP cultures was mTOR-dependent, whereas p27<sup>Kip1</sup> cytoplasmic localization was regulated upstream of mTOR by TSC2. These results indicate that a balance between Shh mitogenic signaling and TSC function regulating new protein synthesis and cyclin-dependent kinase inhibition is essential for the normal development and prevention of tumor formation or expansion. ©2009 American Association for Cancer Research.
Keywords: protein kinase b; controlled study; nonhuman; protein function; protein localization; cell proliferation; animal cell; mouse; animals; mice; animal tissue; cerebellum; sonic hedgehog protein; animal experiment; animal model; hedgehog proteins; enzyme activation; enzyme activity; phosphorylation; mice, inbred c57bl; mice, transgenic; enzyme regulation; brain development; cyclin dependent kinase inhibitor 1b; glycogen synthase kinase 3alpha; glycogen synthase kinase 3beta; hamartin; mammalian target of rapamycin; protein p27; tuberin; enzyme inactivation; gene repression; granule cell; medulloblastoma; carrier proteins; cell growth processes; cerebrum; cyclin-dependent kinase inhibitor p27; phosphotransferases (alcohol group acceptor); tumor suppressor proteins
Journal Title: Cancer Research
Volume: 69
Issue: 18
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2009-09-15
Start Page: 7224
End Page: 7234
Language: English
DOI: 10.1158/0008-5472.can-09-1299
PUBMED: 19738049
PROVIDER: scopus
PMCID: PMC2745891
DOI/URL:
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: CNREA" - "Source: Scopus"
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MSK Authors
  1. Eric Holland
    224 Holland
  2. Bipin Bhatia
    13 Bhatia
  3. Anna Marie Kenney
    34 Kenney