title: Bone morphogenetic protein (BMP) signaling regulates mitotic checkpoint protein levels in human breast cancer cells.
abstract: Aberrant expression of mitotic checkpoint genes compromises mitotic checkpoint, leads to chromosome instability and tumorigenesis. However, the cell signals that control mitotic checkpoint gene expression have not been reported so far. In the present study we show that, in human breast cancer cells, chemical inhibition of Bone morphogenetic proteins (BMPs), but not Transforming Growth Factor-β (TGF-β), abrogates the mitotic arrest induced by nocodazole. Protein expression analysis reveals that inhibition of BMP signaling dramatically down regulates protein levels of mitotic checkpoint components BUB3, Hec1, TTK and MAD2, but inhibition of TGF-β has relatively minor effect on the expression of these proteins. Activation of BMP signaling specifically up regulates BUB3, and activation of Activin A signaling globally down regulates these proteins level. Furthermore, overexpressing MAD2, TTK, BUB3 or Hec1 significantly rescues the mitotic arrest defect caused by BMP inhibition. Our results demonstrated for the first time that TGF-β family cytokines are cellular signals regulating mitotic checkpoint and perturbations in intrinsic BMP signaling could lead to suppression of mitotic checkpoint signaling by downregulating key checkpoint proteins. The results suggest a possible mechanism by which dysregulation of TGF-β signaling causes mitotic checkpoint defects and drives tumorigenesis. The finding also provides a potential and more specific strategy for cancer prevention by targeting BMP and mitotic checkpoint connection.
authors.affiliation: Shanghai Key Laboratory of Signaling and Disease Research at School of Life Science and Technology, Tongji University, No. 1239 Si-ping Road, Shanghai 200092, PR China.
authors.forename: Hualong
authors.initials: H
authors.lastname: Yan
authors.forename: Songcheng
authors.initials: S
authors.lastname: Zhu
authors.forename: Chenlin
authors.initials: C
authors.lastname: Song
authors.forename: Naifa
authors.initials: N
authors.lastname: Liu
authors.forename: Jiuhong
authors.initials: J
authors.lastname: Kang
mesh_terms: D028341:Activins / Q000235:genetics / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004149:Dioxoles / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D064246:Mad2 Proteins; D015739:Nocodazole / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D000075223:Poly-ADP-Ribose Binding Proteins; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C489444:BUB3 protein, human; D001549:Benzamides; D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004149:Dioxoles; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; C120529:NDC80 protein, human; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; C516138:dorsomorphin; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human; D015739:Nocodazole