Cooperative effects of genes controlling the G(2)/M checkpoint.
It is believed that multiple effectors independently control the checkpoints permitting transitions between cell cycle phases. However, this has not been rigorously demonstrated in mammalian cells. The p53-induced genes p21 and 14-3-3sigma are each required for the G(2) arrest and allow a specific test of this fundamental tenet. We generated human cells deficient in both p21 and 14-3-3sigma and determined whether the double knockout was more sensitive to DNA damage than either single knockout. p21(-/-) 14-3-3sigma(-/-) cells were significantly more sensitive to DNA damage or to the exogenous expression of p53 than cells lacking only p21 or only 14-3-3sigma. Thus, p21 and 14-3-3sigma play distinct but complementary roles in the G(2)/M checkpoint, and help explain why genes at the nodal points of growth arrest pathways, like p53, are the targets of mutation in cancer cells.
Chan
T A
TA
Howard Hughes Medical Institute and Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Hwang
P M
PM
Hermeking
H
H
Kinzler
K W
KW
Vogelstein
B
B
D048948:14-3-3 Proteins; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D016195:G2 Phase / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase
D048948:14-3-3 Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D014446:Tyrosine 3-Monooxygenase