title: Amyloid beta protein-related death-inducing protein induces G2/M arrest: Implications for neurodegeneration in Alzheimer's disease.
abstract: Amyloid beta protein (Abeta)-related death-inducing protein (AB-DIP) is a novel Abeta 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.
authors.affiliation: Department of Neuroscience, University of California, San Diego, Leichtag Biomedical Research, La Jolla, California 92093, USA. mlakshma@ucsd.edu
authors.forename: Madepalli K
authors.initials: MK
authors.lastname: Lakshmana
authors.forename: Hideo
authors.initials: H
authors.lastname: Hara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tabira
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D016195:G2 Phase / Q000502:physiology*; D017353:Gene Deletion; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009410:Nerve Degeneration / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014162:Transfection; D050257:Tubulin Modulators / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D050257:Tubulin Modulators; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases