B-cell linker protein prevents aneuploidy by inhibiting cytokinesis.
Aneuploidy is a hallmark of human cancers. Although the maintenance of genomic integrity by p53 is important in preventing aneuploidy, its mechanism remains to be elucidated. Here we report evidence that B-cell linker protein (BLNK) mediates the inhibition of cytokinesis, which generates tetraploidy but prevents aneuploidy. We identified BLNK as a transcriptional target of p53. Surprisingly, ectopic expression of exogenous BLNK inhibited cytokinesis, resulting in the formation of tetraploid cells. Indeed, BLNK was involved in the generation of spontaneously arising binucleate tetraploid cells. Interestingly, cytokinesis after DNA damage was inhibited in p21(-/-) and p53+/+ cells, but not in p53(-/-) cells. BLNK knockdown in p53+/+ and p21(-/-) cells enhanced cytokinesis after DNA damage, leading to the generation of aneuploid cells. In addition, a BLNK-downregulated human pre-B leukemia cell line showed increased cytokinesis and aneuploidy after DNA damage compared with two other pre-B leukemia cell lines expressing higher levels of BLNK. These results suggest that BLNK acts as a mediator of p53 in the inhibition of cytokinesis, which prevents aneuploidy. We propose that the inhibition of cytokinesis is crucial for the maintenance of genomic integrity.
Kamino
Hiroki
H
Cancer Medicine and Biophysics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Futamura
Manabu
M
Nakamura
Yasuyuki
Y
Kitamura
Noriaki
N
Kabu
Koki
K
Arakawa
Hirofumi
H
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000782:Aneuploidy; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D048749:Cytokinesis / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008957:Models, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53