Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.1202607 on May 22, 2003

Published online before print May 22, 2003
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(Journal of Leukocyte Biology. 2003;73:850-861.)
© 2003 by Society for Leukocyte Biology

p53 deficiency and defective mitotic checkpoint in proliferating T lymphocytes increase chromosomal instability through aberrant exit from mitotic arrest

Kwan-Hyuck Baek*, Hyun-Jin Shin*,{dagger}, Jae-Kwang Yoo*, Jae-Ho Cho*, Yo-Han Choi*, Young-Chul Sung*, Frank McKeon{ddagger} and Chang-Woo Lee*,{dagger}

* National Research Laboratory of DNA Medicine, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Korea;
{ddagger} Department of Cell Biology, Harvard Medical School, Boston, Massachusetts; and
{dagger} Research Institute, National Cancer Center, Ilsan-gu, Goyang, Korea

Correspondence: Chang-Woo Lee, Research Institute, National Cancer Center, Ilsan-gu, Goyang, Gyeonggi-do 411-764, Korea. E-mail: cwlee{at}ncc.re.kr

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.

Key Words: cell cycle • proliferation • apoptosis • aneuploid • lymphoma






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