Diana Hom Quon
Eli Lilly and Company
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Featured researches published by Diana Hom Quon.
Neuron | 1995
Jeffrey N. Higaki; Diana Hom Quon; Ziyang Zhong; Barbara Cordell
Cerebral deposition of beta-amyloid protein is a pathological feature central to Alzheimers disease. Production of beta-amyloid by proteolytic processing of the beta-amyloid precursor protein (beta APP) is a critical initial step in beta-amyloidogenesis. We use an inhibitor of beta APP processing to block beta-amyloid peptide formation. Application of the inhibitor to cultured cells results in an accumulation of proteolytic intermediates of beta APP, enabling a precursor-product relationship between beta APP carboxy-terminal fragments and beta-amyloid peptides to be demonstrated directly. In the presence of inhibitor, these amyloidogenic carboxy-terminal fragments can be degraded to nonamyloidogenic products. The catabolism of beta APP carboxy-terminal intermediates and the formation of beta-amyloid peptides are likely to involve an early endosomal compartment as the subcellular site of processing.
Proceedings of the National Academy of Sciences of the United States of America | 2003
Yonghong Li; Hui Wang; Su Wang; Diana Hom Quon; Yu-Wang Liu; Barbara Cordell
Amyloid β peptide (Aβ) generated from amyloid precursor protein (APP) is central to Alzheimers disease (AD). Signaling pathways affecting APP amyloidogenesis play critical roles in AD pathogenesis and can be exploited for therapeutic intervention. Here, we show that sumoylation, covalent modification of cellular proteins by small ubiquitin-like modifier (SUMO) proteins, regulates Aβ generation. Increased protein sumoylation resulting from overexpression of SUMO-3 dramatically reduces Aβ production. Conversely, reducing endogenous protein sumoylation with dominant-negative SUMO-3 mutants significantly increases Aβ production. We also show that mutant SUMO-3, K11R, which can only be monomerically conjugated to target proteins, has an opposite effect on Aβ generation to that by SUMO-3, which can form polymeric chains on target proteins. In addition, SUMO-3 immunoreactivity is predominantly detected in neurons in brains from AD, Downs syndrome, and nondemented humans. Therefore, polysumoylation reduces whereas monosumoylation or undersumoylation enhances Aβ generation. These findings provide a regulatory mechanism in APP amyloidogenesis and suggest that components in the sumoylation pathway may be critical in AD onset or progression.
Biochemical and Biophysical Research Communications | 1990
Diana Hom Quon; Rosanne Catalano; Barbara Cordell
Treatment of PC12 and C6 cell cultures with recombinant basic fibroblast growth factor results in approximately a five to ten-fold stimulation of beta-amyloid precursor mRNA in the C6 astrocytoma cell line but only a slight induction of precursor mRNA in the PC-12 neuronal cell line. Stimulation of expression occurred at a hormone concentration of approximately 0.5 to 1 nM and was seen after 2 days. These results suggest that basic fibroblast growth factor may contribute to amyloidosis of Alzheimers disease.
Journal of Biological Chemistry | 1996
Jeffrey N. Higaki; Rosanne Catalano; Andrew W. Guzzetta; Diana Hom Quon; Jean-François Navé; Celine Tarnus; Hugues d'Orchymont; Barbara Cordell
The events leading to the formation of β-amyloid (βA4) from its precursor (βAPP) involve proteolytic cleavages that produce the amino and carboxyl termini of βA4. The enzyme activities responsible for these cleavages have been termed β- and γ-secretase, respectively, although these protease(s) have not been identified. Since βA4 is known to possess heterogeneity at both the amino and carboxyl termini, β- and γ-secretases may actually be a collection of proteolytic activities or perhaps a single proteolytic enzyme with broad amino acid specificity. We investigated the role of cathepsin D in the processing of βAPP since this enzyme has been widely proposed as a γ-secretase candidate. Treatment of a synthetic peptide that spans the γ-secretase site of βAPP with human cathepsin D resulted in the cleavage of this substrate at Ala42-Thr43. A sensitive liquid chromatography/mass spectrometry technique was also developed to further investigate the ability of cathepsin D to process longer recombinant βAPP substrates (156 and 100 amino acids of βAPP carboxyl terminus) in vitro. The precise cathepsin D cleavage sites within these recombinant βAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. No cleavages were observed at putative γ-secretase sites: Val40-Ile41 or Ala42-Thr43, suggesting that cathepsin D is not γ-secretase as defined by these βA4 termini. Under conditions where the βAPP156 substrate was first denatured prior to cathepsin D digestion, two additional cleavage sites near the amino terminus of βA4, Glu−3-Val−2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of βAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as γ-secretase; however, the ability of this enzyme to efficiently cleave βAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in βAPP catabolism.
Proceedings of the National Academy of Sciences of the United States of America | 1995
L S Higgins; J M Rodems; R Catalano; Diana Hom Quon; Barbara Cordell
Journal of Biological Chemistry | 1995
Asha Naidu; Diana Hom Quon; Barbara Cordell
Archive | 2007
Barbara Cordell; Frauke Schimmoller; Yu-Wang Liu; Diana Hom Quon
Archive | 2000
Ziyang Zhong; Barbara Cordell; Diana Hom Quon; Yu-Wang Liu; Qiang Xu; Frauke Schimmoller; Paul A. Hyslop; Edward M. Johnstone; Sheila P. Little; Stephen Wyatt Queener; Tinggui Yin
Archive | 2001
Barbara Cordell; Frauke Schimmoller; Yu-Wang Liu; Diana Hom Quon
Archive | 2003
Barbara Cordell; Frauke Schimmöoller; Yu-Wang Liu; Diana Hom Quon