PMID- 17170108
OWN - NLM
STAT- MEDLINE
DCOM- 20070326
LR  - 20210306
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 7
DP  - 2007 Feb 16
TI  - RNA interference silencing of the adaptor molecules ShcC and Fe65 differentially 
      affect amyloid precursor protein processing and Abeta generation.
PG  - 4318-4325
LID - S0021-9258(20)65002-5 [pii]
LID - 10.1074/jbc.M609293200 [doi]
AB  - The amyloid precursor protein (APP) and its pathogenic by-product amyloid-beta 
      protein (Abeta) play central roles in Alzheimer disease (AD) neuropathogenesis. 
      APP can be cleaved by beta-secretase (BACE) and alpha-secretase to produce 
      APP-C99 and APP-C83. These C-terminal fragments can then be cleaved by 
      gamma-secretase to produce Abeta and p3, respectively. p3 has been reported to 
      promote apoptosis, and Abeta is the key component of senile plaques in AD brain. 
      APP adaptor proteins with phosphotyrosine-binding domains, including ShcA (SHC1), 
      ShcC (SHC3), and Fe65 (APBB1), can bind to and interact with the conserved YENPTY 
      motif in the APP-C terminus. Here we have described for the first time the 
      effects of RNA interference (RNAi) silencing of ShcA, ShcC, and Fe65 expression 
      on APP processing and Abeta production. RNAi silencing of ShcC led to reductions 
      in the levels of APP-C-terminal fragments (APP-CTFs) and Abeta in H4 human 
      neuroglioma cells stably overexpressing full-length APP (H4-FL-APP cells) but not 
      in those expressing APP-C99 (H4-APP-C99 cells). RNAi silencing of ShcC also led 
      to reductions in BACE levels in H4-FL-APP cells. In contrast, RNAi silencing of 
      the homologue ShcA had no effect on APP processing or Abeta levels. RNAi 
      silencing of Fe65 increased APP-CTF levels, although also decreasing Abeta levels 
      in H4-FL-APP cells. These findings suggest that pharmacologically blocking 
      interaction of APP with ShcC and Fe65 may provide novel therapeutic strategies 
      against AD.
FAU - Xie, Zhongcong
AU  - Xie Z
AD  - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative 
      Disease, Department of Neurology, Charlestown, Massachusetts 02129-2060; 
      Department of Anesthesia and Critical Care, Massachusetts General Hospital and 
      Harvard Medical School, Charlestown, Massachusetts 02129-2060, and.
FAU - Dong, Yuanlin
AU  - Dong Y
AD  - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative 
      Disease, Department of Neurology, Charlestown, Massachusetts 02129-2060; 
      Department of Anesthesia and Critical Care, Massachusetts General Hospital and 
      Harvard Medical School, Charlestown, Massachusetts 02129-2060, and.
FAU - Maeda, Uta
AU  - Maeda U
AD  - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative 
      Disease, Department of Neurology, Charlestown, Massachusetts 02129-2060; 
      Department of Anesthesia and Critical Care, Massachusetts General Hospital and 
      Harvard Medical School, Charlestown, Massachusetts 02129-2060, and.
FAU - Xia, Weiming
AU  - Xia W
AD  - Center for Neurologic Diseases, Harvard Institute of Medicine and Harvard Medical 
      School, Boston, Massachusetts 02115.
FAU - Tanzi, Rudolph E
AU  - Tanzi RE
AD  - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative 
      Disease, Department of Neurology, Charlestown, Massachusetts 02129-2060. 
      Electronic address: tanzi@helix.mgh.harvard.edu.
LA  - eng
GR  - K08 NS 048140-01/NS/NINDS NIH HHS/United States
GR  - K12 AG 000294-17/AG/NIA NIH HHS/United States
GR  - P60 AG 008812-15/AG/NIA NIH HHS/United States
GR  - R01 AG 014713-07/AG/NIA NIH HHS/United States
GR  - R01 MH 60009-03/MH/NIMH NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20061214
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (APBB1 protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Neuropeptides)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (SHC1 protein, human)
RN  - 0 (SHC3 protein, human)
RN  - 0 (Shc Signaling Adaptor Proteins)
RN  - 0 (Src Homology 2 Domain-Containing, Transforming Protein 1)
RN  - 0 (Src Homology 2 Domain-Containing, Transforming Protein 3)
RN  - 0 (amyloid beta-protein p3, human)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/biosynthesis/genetics
MH  - Alzheimer Disease/genetics/metabolism/therapy
MH  - Amyloid Precursor Protein Secretases/*metabolism
MH  - Amyloid beta-Peptides/metabolism
MH  - Amyloid beta-Protein Precursor/*metabolism
MH  - Cell Line, Tumor
MH  - Humans
MH  - Nerve Tissue Proteins/*biosynthesis/genetics
MH  - Neuropeptides/*biosynthesis/genetics
MH  - Nuclear Proteins/*biosynthesis/genetics
MH  - Protein Binding
MH  - *Protein Processing, Post-Translational/genetics
MH  - Protein Structure, Tertiary
MH  - *RNA Interference
MH  - RNA, Small Interfering/genetics
MH  - Shc Signaling Adaptor Proteins
MH  - Species Specificity
MH  - Src Homology 2 Domain-Containing, Transforming Protein 1
MH  - Src Homology 2 Domain-Containing, Transforming Protein 3
EDAT- 2006/12/16 09:00
MHDA- 2007/03/27 09:00
CRDT- 2006/12/16 09:00
PHST- 2006/12/16 09:00 [pubmed]
PHST- 2007/03/27 09:00 [medline]
PHST- 2006/12/16 09:00 [entrez]
AID - S0021-9258(20)65002-5 [pii]
AID - 10.1074/jbc.M609293200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Feb 16;282(7):4318-4325. doi: 10.1074/jbc.M609293200. Epub 2006 
      Dec 14.