Prostate apoptosis response-4 enhances secretion of amyloid beta peptide 1-42 in human neuroblastoma IMR-32 cells by a caspase-dependent pathway.

Prostate apoptosis response-4 enhances secretion of amyloid beta peptide 1-42 in human neuroblastoma IMR-32 cells by a caspase-dependent pathway.

Guo Q; Xie J; Chang X; Du H

The Journal of biological chemistry

2001

2001-05

Prostate apoptosis response-4 (Par-4) is a leucine zipper protein that promotes neuronal cell death in Alzheimer's disease (AD). Neuronal degeneration in AD may result from extracellular accumulation of amyloid beta peptide (Abeta) 1-42. To examine the effect of Par-4 on Abeta secretion and to reconcile amyloid/apoptosis hypotheses of AD, we generated IMR-32 cell lines that overexpress Par-4 and/or its leucine zipper domain. Overexpression of Par-4 did not significantly affect levels of the endogenously expressed beta amyloid precursor protein but drastically increased the Abeta(1-42)/Abeta(total) ratio in the conditioned media about 6-8 h after trophic factor withdrawal. Time course analysis of caspase activation reveals that Par-4 overexpression exacerbated caspase activation, which is detectable within 2 h after trophic factor withdrawal. Furthermore, inhibition of caspase activity by the broad spectrum caspase inhibitor BD-fmk significantly attenuated the Par-4-induced increase in Abeta 1-42 production. In addition, the effects of Par-4 on secretion of Abeta 1-42 were consistently blocked by co-expression of the leucine zipper domain, indicating that the effect of Par-4 on Abeta secretion may require its interaction with other protein(s). These results suggest that Par-4 increases secretion of Abeta 1-42 largely through a caspase-dependent pathway after apoptotic cascades are initiated.

*Intracellular Signaling Peptides and Proteins; Amyloid beta-Peptides/*biosynthesis/metabolism; Apoptosis Regulatory Proteins; Apoptosis/*physiology; Carrier Proteins/genetics/*physiology; Caspases/*metabolism; Cultured; Enzyme Activation; Humans; Kinetics; Leucine Zippers; Neuroblastoma; Peptide Fragments/*biosynthesis/metabolism; Recombinant Proteins/metabolism; Time Factors; Transfection; Tumor Cells

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

16040–16044

19

276