Double trouble: When Sonic hedgehog signaling meets TSC inactivation Journal Article


Authors: Bhatia, B.; Nahlé, Z.; Kenney, A. M.
Article Title: Double trouble: When Sonic hedgehog signaling meets TSC inactivation
Abstract: Certain types of medulloblastoma, the most common solid pediatric cancer, are proposed to arise from neural precursors known as cerebellar granule neuron precursors (CGNPs), which require signaling by Sonic hedgehog (Shh) and insulin-like growth factor (IGF) for their proliferation and survival. Aberrant activity of these pathways is implicated in medulloblastoma. IGF activates the mammalian Target of Rapamycin (mTOR), a growth-promoting kinase normally kept in check by the tumor suppressive Tuberous Sclerosis Complex (TSC), comprised of TSC1 and TSC2. TSC also counteracts proliferation by stabilizing the cyclin-dependent kinase inhibitor p27Kip1, preventing progression through G1- to S-phase of the cell cycle. We reported that mice with impaired TSC activity show increased susceptibility to Shh-mediated medulloblastoma. CGNPs and tumors from these mice display increased proliferation, mTOR pathway activation, glycogen synthase kinase-3 (GSK-3) α/β inactivation, and atypical p27Kip1 cytoplasmic localization. GSK-3α/β inactivation was mTOR-dependent, whereas p27Kip1 localization was uncoupled from mTOR, and was instead regulated by TSC2. These results provide insight into the molecular 'hardwiring' of the mitogenic network downstream of Shh signaling and emphasize the separate yet synergistic effects regulated by the TSC complex in (1) fueling proliferation through mTOR activation/ GSK-3α/β inactivation and (2) compromising checkpoint mechanisms via TSC2-dependent p27Kip1 nuclear exclusion. Future medulloblastoma therapies targeting Shh signaling can be developed to selectively modulate these activities, to restore checkpoint control and attenuate uncontrolled hyperproliferation. © 2010 Landes Bioscience.
Keywords: signal transduction; somatomedin; human cell; nonhuman; cell proliferation; animal cell; mouse; animal; metabolism; mammalia; animals; mice; cerebellum; cell survival; mus; cell cycle progression; cell cycle s phase; biological model; models, biological; sonic hedgehog protein; hedgehog proteins; pathology; cyclin dependent kinase inhibitor 1b; mammalian target of rapamycin; tuberin; enzyme inactivation; medulloblastoma; cyclin-dependent kinase inhibitor p27; tumor suppressor proteins; gene silencing; tumor suppressor protein; disease predisposition; sonic hedgehog; erinaceidae; cell cycle g1 phase; tuberous sclerosis; mtor; glycogen synthase kinase 3; p27kip1; tsc; tuberous sclerosis complex 1 protein
Journal Title: Cell Cycle
Volume: 9
Issue: 3
ISSN: 1538-4101
Publisher: Taylor & Francis Inc.  
Date Published: 2010-02-01
Start Page: 456
End Page: 459
Language: English
PUBMED: 20081363
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Bipin Bhatia
    13 Bhatia
  2. Anna Marie Kenney
    34 Kenney