AATF inhibits aberrant production of amyloid beta peptide 1-42 by interacting directly with Par-4.
Aggregation of the neurotoxic amyloid beta peptide 1-42 (Abeta-(1-42)) in the brain is considered to be an early event in the pathogenesis of Alzheimer's disease (AD). Par-4 (prostate apoptosis response-4) is a leucine zipper protein that is pro-apoptotic and associated with neuronal degeneration in AD. Overexpression of Par-4 significantly increased ... production of Abeta-(1-42) after initiation of apoptotic cascades, indicating factors regulating apoptotic pathways may also affect processing of beta-amyloid precursor protein (APP). AATF (apoptosis-antagonizing transcription factor) was recently identified as an interaction partner of DAP-like kinase (Dlk), a member of the DAP (death-associated protein) kinase family. AATF antagonizes apoptosis induced by Par-4, suggesting that AATF might directly or indirectly participate in regulation of Par-4 activity. We now report that AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments, and it interacts directly and selectively with Par-4 via the leucine zipper domain in neural cells. Par-4 induced an aberrant production and secretion of Abeta in neuroblastoma IMR-32 cells after apoptotic cascades are initiated. Co-expression of AATF completely blocked aberrant production and secretion of Abeta-(1-42) induced by Par-4, and AATF/Par-4 complex formation was essential for the inhibitory effect of AATF on aberrant Abeta secretion. These results indicate that AATF is an endogenous antagonist of Par-4 activity and an effective inhibitor of aberrant Abeta production and secretion under apoptotic conditions.
Mesh Terms:
Alzheimer Disease, Amyloid beta-Protein, Animals, Apoptosis, Apoptosis Regulatory Proteins, Carrier Proteins, Cell Nucleus, Cells, Cultured, Cytoplasm, Hippocampus, Humans, Intracellular Signaling Peptides and Proteins, Leucine Zippers, Mice, Nerve Degeneration, Peptide Fragments, Protein Structure, Tertiary, Recombinant Proteins, Repressor Proteins, Transcription Factors
Alzheimer Disease, Amyloid beta-Protein, Animals, Apoptosis, Apoptosis Regulatory Proteins, Carrier Proteins, Cell Nucleus, Cells, Cultured, Cytoplasm, Hippocampus, Humans, Intracellular Signaling Peptides and Proteins, Leucine Zippers, Mice, Nerve Degeneration, Peptide Fragments, Protein Structure, Tertiary, Recombinant Proteins, Repressor Proteins, Transcription Factors
J. Biol. Chem.
Date: Feb. 06, 2004
PubMed ID: 14627703
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