Linked Life Data

20081363

Source:http://linkedlifedata.com/resource/pubmed/id/20081363

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2010-2-22
pubmed:abstractText
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 p27(Kip1), preventing progression through G(1)- 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) alpha/beta inactivation, and atypical p27(Kip1) cytoplasmic localization. GSK-3alpha/beta inactivation was mTOR-dependent, whereas p27(Kip1) 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-3alpha/beta inactivation and (2) compromising checkpoint mechanisms via TSC2-dependent p27(Kip1) nuclear exclusion. Future medulloblastoma therapies targeting Shh signaling can be developed to selectively modulate these activities, to restore checkpoint control and attenuate uncontrolled hyperproliferation.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1551-4005
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
456-9
pubmed:dateRevised
2010-8-25
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Double trouble: when sonic hedgehog signaling meets TSC inactivation.
pubmed:affiliation
Department of Cancer Biology and Genetics and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural