PDZ domain-dependent suppression of NF-kappaB/p65-induced Abeta42 production by a neuron-specific X11-like protein.

It is widely believed that one of the causes of Alzheimer's disease (AD) is the generation and secretion of beta-amyloid (Abeta) from amyloid precursor protein in the brain. Here we report that a transcription factor, NF-kappaB/p65, induces increased secretion of amyloidogenic Abeta42 but not Abeta40. The kappaB motif-dependent production of ...
Abeta42 was suppressed by binding of NF-kappaB/p65 to the PDZ domain of the X11-like protein (X11L), which a human homologue protein of LIN-10. The results suggest that the PDZ domain of X11L can control the ability of NF-kappaB/p65 to induce expression of protein(s) involved in Abeta42 production. The amino acids 161-163 in Rel homology domain (RHD) of NF-kappaB/p65 is important in interaction of NF-kappaB/p65 with X11L. Another subunit NF-kappaB/p50 and heterodimers of p65 and p50 do not bind to X11L. Our finding indicates NF-kappaB and X11L may, in novel way, regulate Abeta production in neuronal cells. Targeting X11L by specific therapy may provide the possibility to control the progression of AD.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amyloid beta-Protein, Animals, Brain, COS Cells, Cell Line, DNA, Complementary, Gene Expression Regulation, Gene Library, Humans, Luciferases, NF-kappa B, NF-kappa B p50 Subunit, Nerve Tissue Proteins, Neurons, Peptide Fragments, Precipitin Tests, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Transcription Factor RelA, Transcription, Genetic, Transfection, Two-Hybrid System Techniques
J. Biol. Chem.
Date: Apr. 28, 2000
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