title: Expression of oncogenic kinase Bcr-Abl impairs mitotic checkpoint and promotes aberrant divisions and resistance to microtubule-targeting agents.
abstract: Recent findings showed that BRCA1, in addition to its role in DNA damage response, acts as an upstream regulator of genes involved in the mitotic checkpoint regulation, thus protecting against promotion of aberrant divisions and aneuploidy. Moreover, there is also an indication that the BRCA1 protein is downregulated in chronic myeloid leukemia (CML) patients. We have investigated a possible functional relationship between BRCA1 and mitotic checkpoint competence in cells with the same genetic background expressing different levels of Bcr-Abl, an oncogene responsible for CML. Herein, we show that Bcr-Abl strongly downregulates the BRCA1 protein level, which is partially reversed on treatment with imatinib, an inhibitor of Bcr-Abl tyrosine kinase. Bcr-Abl leads to decreased expression of genes involved in the mitotic checkpoint activation--Mad2, Bub1, Bub3, and BubR1, resulting in mitosis perturbances, weakened mitotic checkpoint function, and mitotic slippage after nocodazole treatment. Furthermore, high Bcr-Abl-expressing cells showed also postmitotic checkpoint dysfunctions and inability to effectively arrest in the 4NG1 phase of the cell cycle, which was associated with limited p21 induction. These observations had significant biological consequences, as we found a high level of improper divisions, chromosomal missegregation, and generation of polyploid cells on mitotic checkpoint prolonged activation. Additionally, Bcr-Abl-expressing cells showed resistance to death activated by spindle defects, reversed by imatinib. Our study presents new facts and supports the hypothesis concerning the mutator nature of Bcr-Abl itself. The functional interaction between Bcr-Abl and mitosis dysfunctions, due to compromised mitotic checkpoints, may have important implications for the generation of aneuploidy and CML progression.
authors.affiliation: Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Kamila
authors.initials: K
authors.lastname: Wolanin
authors.forename: Adriana
authors.initials: A
authors.lastname: Magalska
authors.forename: Monika
authors.initials: M
authors.lastname: Kusio-Kobialka
authors.forename: Paulina
authors.initials: P
authors.lastname: Podszywalow-Bartnicka
authors.forename: Susanne
authors.initials: S
authors.lastname: Vejda
authors.forename: Sharon L
authors.initials: SL
authors.lastname: McKenna
authors.forename: Grazyna
authors.initials: G
authors.lastname: Mosieniak
authors.forename: Ewa
authors.initials: E
authors.lastname: Sikora
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Piwocka
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002455:Cell Division / Q000235:genetics*; D002478:Cells, Cultured; D018450:Disease Progression; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D018816:Genes, cdc / Q000502:physiology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D050257:Tubulin Modulators; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl