PMID- 14660435
OWN - NLM
STAT- MEDLINE
DCOM- 20040303
LR  - 20101118
IS  - 0950-1991 (Print)
IS  - 0950-1991 (Linking)
VI  - 131
IP  - 1
DP  - 2004 Jan
TI  - Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle 
      progression in cerebellar neuronal precursors.
PG  - 217-28
AB  - Neuronal precursor cells in the developing cerebellum require activity of the 
      sonic hedgehog (Shh) and phosphoinositide-3-kinase (PI3K) pathways for growth and 
      survival. Synergy between the Shh and PI3K signaling pathways are implicated in 
      the cerebellar tumor medulloblastoma. Here, we describe a mechanism through which 
      these disparate signaling pathways cooperate to promote proliferation of 
      cerebellar granule neuron precursors. Shh signaling drives expression of mRNA 
      encoding the Nmyc1 oncoprotein (previously N-myc), which is essential for 
      expansion of cerebellar granule neuron precursors. The PI3K pathway stabilizes 
      Nmyc1 protein via inhibition of GSK3-dependent Nmyc1 phosphorylation and 
      degradation. The effects of PI3K activity on Nmyc1 stabilization are mimicked by 
      insulin-like growth factor, a PI3K agonist with roles in central nervous system 
      precursor growth and tumorigenesis. These findings indicate that Shh and PI3K 
      signaling pathways converge on N-Myc to regulate neuronal precursor cell cycle 
      progression. Furthermore, they provide a rationale for therapeutic targeting of 
      PI3K signaling in medulloblastoma.
FAU - Kenney, Anna Marie
AU  - Kenney AM
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard 
      Medical School, Boston, MA 02115, USA.
FAU - Widlund, Hans R
AU  - Widlund HR
FAU - Rowitch, David H
AU  - Rowitch DH
LA  - eng
GR  - R01 NS4051/NS/NINDS NIH HHS/United States
GR  - R21 NS41764-01/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20031203
PL  - England
TA  - Development
JT  - Development (Cambridge, England)
JID - 8701744
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Shh protein, mouse)
RN  - 0 (Trans-Activators)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
SB  - IM
EIN - Development. 2004 Jan;131(2):489
MH  - Animals
MH  - Animals, Newborn
MH  - Cell Cycle/*physiology
MH  - Cell Differentiation
MH  - Cerebellum/cytology/*physiology
MH  - Hedgehog Proteins
MH  - Mice
MH  - Neurons/cytology/*physiology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Signal Transduction/*physiology
MH  - Stem Cells/cytology/*physiology
MH  - Trans-Activators/*metabolism
EDAT- 2003/12/09 05:00
MHDA- 2004/03/05 05:00
CRDT- 2003/12/09 05:00
PHST- 2003/12/09 05:00 [pubmed]
PHST- 2004/03/05 05:00 [medline]
PHST- 2003/12/09 05:00 [entrez]
AID - dev.00891 [pii]
AID - 10.1242/dev.00891 [doi]
PST - ppublish
SO  - Development. 2004 Jan;131(1):217-28. doi: 10.1242/dev.00891. Epub 2003 Dec 3.