PMID- 20081363
OWN - NLM
STAT- MEDLINE
DCOM- 20100504
LR  - 20200930
IS  - 1551-4005 (Electronic)
IS  - 1551-4005 (Linking)
VI  - 9
IP  - 3
DP  - 2010 Feb 1
TI  - Double trouble: when sonic hedgehog signaling meets TSC inactivation.
PG  - 456-9
AB  - 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.
FAU - Bhatia, Bobby
AU  - Bhatia B
AD  - Department of Cancer Biology and Genetics and Brain Tumor Center, Memorial 
      Sloan-Kettering Cancer Center, New York, NY, USA.
FAU - Nahle, Zaher
AU  - Nahle Z
FAU - Kenney, Anna Marie
AU  - Kenney AM
LA  - eng
GR  - R01NS061070/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100206
PL  - United States
TA  - Cell Cycle
JT  - Cell cycle (Georgetown, Tex.)
JID - 101137841
RN  - 0 (Hedgehog Proteins)
RN  - 0 (TSC1 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
SB  - IM
MH  - Animals
MH  - Cyclin-Dependent Kinase Inhibitor p27/metabolism
MH  - *Gene Silencing
MH  - Hedgehog Proteins/*metabolism
MH  - Humans
MH  - Medulloblastoma/pathology
MH  - Mice
MH  - Models, Biological
MH  - *Signal Transduction
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/*metabolism
EDAT- 2010/01/19 06:00
MHDA- 2010/05/05 06:00
CRDT- 2010/01/19 06:00
PHST- 2010/01/19 06:00 [entrez]
PHST- 2010/01/19 06:00 [pubmed]
PHST- 2010/05/05 06:00 [medline]
AID - 10532 [pii]
AID - 10.4161/cc.9.3.10532 [doi]
PST - ppublish
SO  - Cell Cycle. 2010 Feb 1;9(3):456-9. doi: 10.4161/cc.9.3.10532. Epub 2010 Feb 6.