Widespread genomic instability mediated by a pathway involving glycoprotein Ib alpha and Aurora B kinase.
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.
Li
Youjun
Y
Section of Hematology/Oncology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15201, USA.
Xu
Fengfeng L
FL
Lu
Jie
J
Saunders
William S
WS
Prochownik
Edward V
EV
D064107:Aurora Kinase B; D064127:Aurora Kinases; D002460:Cell Line; D048749:Cytokinesis / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics; D019038:Platelet Glycoprotein GPIb-IX Complex; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D008562:Membrane Glycoproteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C094990:adhesion receptor; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases