Widespread Genomic Instability Mediated by a Pathway Involving Glycoprotein Ibα and Aurora B Kinase
| Autor: | Edward V. Prochownik, Williams S. Saunders, Youjun Li, Jie Lu, Fengfeng L. Xu |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Aurora inhibitor
Aurora B kinase Down-Regulation Mitosis macromolecular substances Protein Serine-Threonine Kinases Biology Biochemistry Genomic Instability Cell Line Polyploidy Proto-Oncogene Proteins c-myc Aurora Kinases Aurora Kinase B Humans Endoreduplication DNA Breaks Double-Stranded Cleavage furrow Molecular Biology Cytokinesis Membrane Glycoproteins Cell Biology Fibroblasts Molecular biology Chromatin Cell biology Platelet Glycoprotein GPIb-IX Complex embryonic structures Tumor Suppressor Protein p53 Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 285:13183-13192 |
| ISSN: | 0021-9258 |
| Popis: | c-Myc (Myc) oncoprotein induction of genomic instability (GI) contributes to its initial transforming function and subsequent tumor cell evolution. We describe here a pathway by which Myc, via its target protein glycoprotein Ibalpha (GpIb alpha), mediates GI. Proteomic profiling revealed that the serine/threonine kinase Aurora B is down-regulated by GpIb alpha in p53-deficient primary human fibroblasts. The phenotypes of Aurora B deficiency are strikingly reminiscent of Myc or GpIb alpha overexpression and include double-stranded DNA breaks, altered nuclear size and morphology, chromatin bridges, cleavage furrow regression, and tetraploidy. During mitosis, GpIb alpha and Aurora B redistribute to the cleavage furrow along with other cleavage furrow proteins. GpIb alpha overexpression at levels comparable with those seen in some tumor cells causes the dispersal of these proteins but not Aurora B, resulting in furrow regression and cytokinesis failure. Aurora B normalization redirects the mislocalized furrow proteins to their proper location, corrects the cleavage furrow abnormalities, and restores genomic stability. Aurora B thus appears necessary for a previously unrecognized function in guiding and positioning a number of key proteins, including GpIb alpha to the cleavage furrow. These findings underscore the importance of maintaining a delicate balance among cleavage furrow-associated proteins during mitosis. Suppression of Aurora B via GpIb alpha provides a unifying and mechanistic explanation for several types of Myc-mediated GI. |
| Databáze: | OpenAIRE |
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