title: The ARF tumor suppressor prevents chromosomal instability and ensures mitotic checkpoint fidelity through regulation of Aurora B.
abstract: The ARF tumor suppressor is part of the CDKN2A locus and is mutated or undetectable in numerous cancers. The best-characterized role for ARF is in stabilizing p53 in response to cellular stress. However, ARF has tumor suppressive functions outside this pathway that have not been fully defined. Primary mouse embryonic fibroblasts (MEFs) lacking the ARF tumor suppressor contain abnormal numbers of chromosomes. However, no role for ARF in cell division has previously been proposed. Here we demonstrate a novel, p53-independent role for ARF in the mitotic checkpoint. Consistent with this, loss of ARF results in aneuploidy in vitro and in vivo. ARF(-/-) MEFs exhibit mitotic defects including misaligned and lagging chromosomes, multipolar spindles, and increased tetraploidy. ARF(-/-) cells exhibit overexpression of Mad2, BubR1, and Aurora B, but only overexpression of Aurora B phenocopies mitotic defects observed in ARF(-/-) MEFs. Restoring Aurora B to near-normal levels rescues mitotic phenotypes in cells lacking ARF. Our results define an unexpected role for ARF in chromosome segregation and mitotic checkpoint function. They further establish maintenance of chromosomal stability as one of the additional tumor-suppressive functions of ARF and offer a molecular explanation for the common up-regulation of Aurora B in human cancers.
authors: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53705 Molecular and Cellular Pharmacology Training Program, University of Wisconsin, Madison, WI 53705.
authors: Eric M C
authors: EM
authors: Britigan
authors: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53705 Physiology Training Program, University of Wisconsin, Madison, WI 53705.
authors: Jun
authors: J
authors: Wan
authors: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53705 Molecular and Cellular Pharmacology Training Program, University of Wisconsin, Madison, WI 53705.
authors: Lauren M
authors: LM
authors: Zasadil
authors: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53705.
authors: Sean D
authors: SD
authors: Ryan
authors: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53705 Carbone Cancer Center, University of Wisconsin, Madison, WI 53705 baweaver@wisc.edu.
authors: Beth A
authors: BA
authors: Weaver
mesh_terms: D000782:Aneuploidy; D000818:Animals; D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D043171:Chromosomal Instability; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D004795:Enzyme Stability; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006207:Half-Life; D064246:Mad2 Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C584278:Bub1b protein, mouse; C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D017346:Protein Serine-Threonine Kinases