PMID- 16505167
OWN - NLM
STAT- MEDLINE
DCOM- 20060406
LR  - 20181113
IS  - 0021-9525 (Print)
IS  - 1540-8140 (Electronic)
IS  - 0021-9525 (Linking)
VI  - 172
IP  - 5
DP  - 2006 Feb 27
TI  - Autophagy-mediated clearance of huntingtin aggregates triggered by the 
      insulin-signaling pathway.
PG  - 719-31
AB  - Conditional mouse models of polyglutamine diseases, such as Huntington's disease 
      (HD), have revealed that cells can clear accumulated pathogenic proteins if the 
      continuous production of the mutant transgene is halted. Invariably, the 
      clearance of the protein leads to regression of the disease symptoms in mice. In 
      light of these findings, it is critical to determine the pathway responsible for 
      alleviating this protein accumulation to define targets to fight these diseases. 
      In a functional genetic screen of HD, we found that activation of insulin 
      receptor substrate-2, which mediates the signaling cascades of insulin and 
      insulin-like growth factor 1, leads to a macroautophagy-mediated clearance of the 
      accumulated proteins. The macroautophagy is triggered despite activation of Akt, 
      mammalian target of rapamycin (mTOR), and S6 kinase, but still requires proteins 
      previously implicated in macroautophagy, such as Beclin1 and hVps34. These 
      findings indicate that the accumulation of mutant protein can lead to 
      mTOR-independent macroautophagy and that lysosome-mediated degradation of 
      accumulated protein differs from degradation under conditions of starvation.
FAU - Yamamoto, Ai
AU  - Yamamoto A
AD  - The Judith P. Sulzberger Columbia Genome Center, Department of Physiology and 
      Cellular Biophysics, Columbia University, New York, NY 10032, USA.
FAU - Cremona, M Laura
AU  - Cremona ML
FAU - Rothman, James E
AU  - Rothman JE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Biol
JT  - The Journal of cell biology
JID - 0375356
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Beclin-1)
RN  - 0 (Becn1 protein, mouse)
RN  - 0 (Htt protein, mouse)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Irs2 protein, mouse)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis Regulatory Proteins
MH  - Autophagy/*physiology
MH  - Beclin-1
MH  - Cell Line
MH  - Gene Expression Profiling
MH  - Huntingtin Protein
MH  - Insulin/*physiology
MH  - Insulin Receptor Substrate Proteins
MH  - Intracellular Signaling Peptides and Proteins
MH  - Mice
MH  - Mutation
MH  - Nerve Tissue Proteins/genetics/*metabolism
MH  - Nuclear Proteins/genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinases/physiology
MH  - Phosphoproteins/physiology
MH  - Proteins/physiology
MH  - RNA, Small Interfering
MH  - Signal Transduction/*physiology
PMC - PMC2063704
EDAT- 2006/03/01 09:00
MHDA- 2006/04/07 09:00
PMCR- 2006/08/27
CRDT- 2006/03/01 09:00
PHST- 2006/03/01 09:00 [pubmed]
PHST- 2006/04/07 09:00 [medline]
PHST- 2006/03/01 09:00 [entrez]
PHST- 2006/08/27 00:00 [pmc-release]
AID - jcb.200510065 [pii]
AID - 200510065 [pii]
AID - 10.1083/jcb.200510065 [doi]
PST - ppublish
SO  - J Cell Biol. 2006 Feb 27;172(5):719-31. doi: 10.1083/jcb.200510065.