Impaired phosphorylation and mis-localization of Bub1 and BubR1 are responsible for the defective mitotic checkpoint function in Brca2-mutant thymic lymphomas.
Breast cancer susceptibility gene, BRCA2, is a tumor suppressor and individuals who inherit one defected copy of BRCA2 allele experience early onset breast cancer or ovarian cancer accompanied by the loss of the wild type allele. Mouse model for Brca2 mutation shows growth retardation and paradoxical occurrence of thymic lymphomas. Thymic lymphomas from Brca2-mutant mice harbor mutations in p53, Bub1, and BubR1, which function as mitotic checkpoint proteins. Therefore, interplay between Brca2 and mitotic checkpoint has been suggested in the maintenance of genetic fidelity, although it has not been assessed whether the unique mutations in Bub1 and BubR1 found in Brca2-mutant mice are responsible for the abolishment of mitotic checkpoint function. This report demonstrates that Bub1 and BubR1 mutant proteins from Brca2-/- thymic lymphomas have defects in the phosphorylation and kinetochore localization after spindle damage. Thus, the mutations of Bub1 and BubR1 found in Brca2- mutant mice indeed are responsible for the chromosome instability in Brca2-mutated tumors.
Lee
Hyunsook
H
Division of Molecular Life Sciences, Ewha Womans University, 11-1 Daehyun-dong, Seodaemoon-gu, Seoul 120-750, Korea. hyunlee@ewha.ac.kr
D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D051379:Mice; D008938:Mitosis; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport; D013601:T-Lymphocytes / Q000378:metabolism; D013953:Thymus Neoplasms / Q000235:genetics / Q000473:pathology*
D024682:BRCA2 Protein; C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D011494:Protein Kinases; C584281:Bub1 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases