p53 deficiency and defective mitotic checkpoint in proliferating T lymphocytes increase chromosomal instability through aberrant exit from mitotic arrest.
During the proliferation of T cells for successful immune responses against pathogens, the fine regulation of cell cycle is important to the maintenance of T cell homeostasis and the prevention of lymphoproliferative disorders. However, it remains to be elucidated how the cell cycle is controlled at the mitotic phase in proliferating T cells. Here, we show that during the proliferation of primary T cells, the disruption of the mitotic spindle leads to cell-cycle arrest at mitosis and that prolonged mitotic arrest results in not only apoptosis but also the form of chromosomal instability observed in human cancers. It is interesting that in response to spindle damage, the phosphorylation of BubR1, a mitotic checkpoint kinase, was significantly induced in proliferating T cells, and the expression of the dominant-negative mutant of BubR1 compromised mitotic arrest and subsequent apoptosis and thus led to the augmentation of polyploidy formation. We also show that in response to prolonged spindle damage, the expression of p53 but not of p73 was significantly induced. In addition, following sustained mitotic arrest, p53-deficient T cells were found to be more susceptible to polyploidy formation than the wild type. These results suggest that during flourishing immune response, mitotic checkpoint and p53 play important roles in the prevention of chromosomal instability and in the maintenance of the genomic integrity of proliferating T cells.
Baek
Kwan-Hyuck
KH
National Research Laboratory of DNA Medicine, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Korea.
Shin
Hyun-Jin
HJ
Yoo
Jae-Kwang
JK
Cho
Jae-Ho
JH
Choi
Yo-Han
YH
Sung
Young-Chul
YC
McKeon
Frank
F
Lee
Chang-Woo
CW
D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002875:Chromosomes; D004247:DNA / Q000032:analysis; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008938:Mitosis; D009154:Mutation; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011123:Polyploidy; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D008941:Spindle Apparatus / Q000187:drug effects; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel; D015739:Nocodazole