PMID- 21339731
OWN - NLM
STAT- MEDLINE
DCOM- 20110616
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 30
IP  - 15
DP  - 2011 Apr 14
TI  - Divergent functions for eIF4E and S6 kinase by sonic hedgehog mitogenic signaling 
      in the developing cerebellum.
PG  - 1784-97
LID - 10.1038/onc.2010.564 [doi]
AB  - Cerebellar development entails rapid peri-natal proliferation of cerebellar 
      granule neuron precursors (CGNPs), proposed cells-of-origin for certain 
      medulloblastomas. CGNPs require insulin-like growth factor (IGF) for survival and 
      sonic hedgehog (Shh)-implicated in medulloblastoma-for proliferation. The 
      IGF-responsive kinase mammalian target of rapamycin (mTOR) drives 
      proliferation-associated protein synthesis. We asked whether Shh signaling 
      regulates mTOR targets to promote CGNP proliferation despite constitutive IGF 
      signaling under proliferative and differentiation-promoting conditions. 
      Surprisingly, Shh promoted eukaryotic initiation factor 4E (eIF4E) expression, 
      but inhibited S6 kinase (S6K). In vivo, S6K activity specifically marked the CGNP 
      population transitioning from proliferation-competent to post-mitotic. Indeed, 
      eIF4E was required for CGNP proliferation, while S6K activation drove cell cycle 
      exit. Protein phosphatase 2A (PP2A) inhibition rescued S6K activity. Moreover, 
      Shh upregulated the PP2A B56gamma subunit, which targets S6K for inactivation and was 
      required for CGNP proliferation. These findings reveal unique developmental 
      functions for eIF4E and S6 kinase wherein their activity is specifically 
      uncoupled by mitogenic Shh signaling.
FAU - Mainwaring, L A
AU  - Mainwaring LA
AD  - Biochemistry, Cell, and Molecular Biology Program, Weill Medical College of 
      Cornell University, New York, NY, USA.
FAU - Kenney, A M
AU  - Kenney AM
LA  - eng
GR  - R01 NS061070/NS/NINDS NIH HHS/United States
GR  - R01 NS061070-05/NS/NINDS NIH HHS/United States
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 - 20110221
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Mitogens)
RN  - 0 (Shh protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Cycle
MH  - Cell Proliferation
MH  - Cerebellum/*growth & development
MH  - Eukaryotic Initiation Factor-4E/*metabolism
MH  - Hedgehog Proteins/*metabolism
MH  - Mice
MH  - Mitogens/*metabolism
MH  - Ribosomal Protein S6 Kinases/*metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC3583293
MID - NIHMS287627
EDAT- 2011/02/23 06:00
MHDA- 2011/06/17 06:00
PMCR- 2013/02/27
CRDT- 2011/02/23 06:00
PHST- 2011/02/23 06:00 [entrez]
PHST- 2011/02/23 06:00 [pubmed]
PHST- 2011/06/17 06:00 [medline]
PHST- 2013/02/27 00:00 [pmc-release]
AID - onc2010564 [pii]
AID - 10.1038/onc.2010.564 [doi]
PST - ppublish
SO  - Oncogene. 2011 Apr 14;30(15):1784-97. doi: 10.1038/onc.2010.564. Epub 2011 Feb 
      21.