Amyloid beta protein-related death-inducing protein induces G2/M arrest: Implications for neurodegeneration in Alzheimer's disease

✍ Scribed by Madepalli K. Lakshmana; Hideo Hara; Takeshi Tabira

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 753 KB
• Volume: 85
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.21351

✦ Synopsis

Abstract

Amyloid beta protein (Aβ)‐related death‐inducing protein (AB‐DIP) is a novel Aβ binding protein expressed ubiquitously. Here we demonstrate that overexpression of AB‐DIP in SH‐SY5Y neuroblastoma cells causes G2/M arrest. By deletion mutant analysis, we have identified the minimal region within AB‐DIP required for G2/M arrest. We have also shown that microtubule‐interfering agents (MIAs) such as nocodazole, vinblastine, paclitaxel, and vincristine, known to arrest cells at G2/M, also phosphorylate AB‐DIP. However, etoposide, which causes genotoxic stress; tunicamycin, an ER stress inducer; and rotenone, which causes mitochondrial damage, fail to phosphorylate AB‐DIP, implying that phosphorylation of AB‐DIP is specific to microtubule‐disruption‐induced G2/M arrest. By using different classes of kinase inhibitors, we also demonstrate that a putative tyrosine kinase phosphorylates AB‐DIP. Mono‐ or multisite mutations of tyrosine or serine/threonine residues confirmed that mutation of tyrosine residues but not serine/threonine residues greatly reduces nocodazole‐induced phosphorylation of AB‐DIP. Furthermore, phosphorylation of AB‐DIP can be induced in MCF‐7 cells that lack functional p53, suggesting that AB‐DIP phosphorylation is independent of p53. Mounting experimental evidence continues to support the role of cell cycle abnormalities in the pathogenesis of Alzheimer's disease, and our results suggest that AB‐DIP might provide a mechanistic link between microtubule disruption, mitotic abnormalities, neuronal dysfunction, and death. Therefore, interfering with AB‐DIP may have therapeutic applications in conditions such as Alzheimer's disease, in which microtubule disruption and mitotic abnormalities have been suggested to play a pathological role. © 2007 Wiley‐Liss, Inc.