Cross-talk between Chk1 and Chk2 in double-mutant thymocytes.
Chk1 is a checkpoint kinase and an important regulator of mammalian cell division. Because null mutation of Chk1 in mice is embryonic lethal, we used the Cre-loxP system and the Lck promoter to generate conditional mutant mice in which Chk1 was deleted only in the T lineage. In the absence of Chk1, the transition of CD4(-)CD8(-) double-negative (DN) thymocytes to CD4(+)CD8(+) double-positive (DP) cells was blocked due to an increase in apoptosis at the DN2 and DN3 stages. Strikingly, loss of Chk1 activated the checkpoint kinase Chk2 as well as the tumor suppressor p53 in these thymocytes. However, the developmental defects caused by Chk1 deletion were not rescued by p53 inactivation. Significantly, even though Chk1 deletion is highly lethal in proliferating tissues, we succeeded in using in vivo methods to generate Chk1/Chk2 double-knockout T cells. Analysis of these T cells revealed an interesting interaction between Chk1 and Chk2 functions that partially rescued the apoptosis of the double-mutant cells. Thus, Chk1 is both critical for the survival of proliferating cells and engages in cross-talk with the Chk2 checkpoint kinase pathway. These factors have implications for the targeting of Chk1 as an anticancer therapy.
Zaugg
Kathrin
K
Campbell Family Institute for Breast Cancer Research, 620 University Avenue, Suite 706, Toronto, Ontario, Canada M5G 2C1.
Su
Yu-Wen
YW
Reilly
Patrick T
PT
Moolani
Yasmin
Y
Cheung
Carol C
CC
Hakem
Razquallah
R
Hirao
Atsushi
A
Liu
Qinghua
Q
Elledge
Stephen J
SJ
Mak
Tak W
TW
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019070:Cell Lineage; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases