B-cell linker protein prevents aneuploidy by inhibiting cytokinesis.

Abstract

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.

• Authors: Hiroki Kamino, Manabu Futamura, Yasuyuki Nakamura, Noriaki Kitamura, Koki Kabu, Hirofumi Arakawa
• Journal: Cancer science (Cancer Sci) Vol. 99 Issue 12 Pg. 2444-54 (Dec 2008) ISSN: 1349-7006 [Electronic] England
• PMID: 19018766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• B cell linker protein
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Tumor Suppressor Protein p53

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Aneuploidy
• Carcinoma, Hepatocellular (genetics, pathology)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (genetics)
• Cytokinesis (genetics)
• HCT116 Cells
• Humans
• In Situ Hybridization, Fluorescence
• Liver Neoplasms (genetics, pathology)
• Models, Genetic
• Tumor Suppressor Protein p53 (genetics)