ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis

J Neurochem. 2003 May;85(3):801-9. doi: 10.1046/j.1471-4159.2003.01727.x.


APP-BP1, first identified as a protein that interacts with the carboxyl (C) terminus of the amyloid precursor protein (APP), is one-half of the bipartite activating enzyme for the ubiquitin-like protein NEDD8. We report here that APP-BP1 also specifically interacts with apoptosis stimulating protein of p53 ASPP2 in non-transfected cells through the functional predominant N-terminal domain ASPP2(332-483). ASPP2 inhibits the ability of APP-BP1 to rescue the ts41 cell cycle mutation and inhibits APP-BP1 induced apoptosis in primary neurons. ASPP2 reduces the ability of NEDD8 to conjugate to Cullin-1, inhibits APP-BP1-dependent ts41 cell proliferation, and blocks the ability of APP-BP1 to cause apoptosis and to cause DNA synthesis in neurons. We also show that ASPP2 activates nuclear factor-kappaB (NF-kappaB) transcriptional activity, which seems to be inhibited by the neddylation pathway since the dominant negative NEDD8 activating enzyme causes enhanced NF-kappaB activity. Our data provide the first in vivo evidence that ASPP2 is a negative regulator of the neddylation pathway through specific interaction with APP-BP1 and suggest that dysfunction of the APP-BP1 interaction with APP may be one cause of Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Carrier Proteins / pharmacology*
  • Cell Cycle Proteins / metabolism*
  • Cell Division / drug effects
  • Cells, Cultured
  • Cricetinae
  • Cullin Proteins*
  • DNA / biosynthesis
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / pharmacology*
  • Humans
  • Macromolecular Substances
  • NEDD8 Protein
  • NF-kappa B / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Protein Binding
  • Protein Subunits / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology
  • Ubiquitin-Activating Enzymes
  • Ubiquitins / metabolism*


  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cullin 1
  • Cullin Proteins
  • DNA-Binding Proteins
  • Macromolecular Substances
  • NEDD8 Protein
  • NEDD8 protein, human
  • NF-kappa B
  • Protein Subunits
  • TP53BP2 protein, human
  • Ubiquitins
  • DNA
  • Ubiquitin-Activating Enzymes
  • NAE protein, human