14-3-3sigma is a p53-regulated inhibitor of G2/M progression.
Exposure of colorectal cancer (CRC) cells to ionizing radiation results in a cell-cycle arrest in G1 and G2. The G1 arrest is due to p53-mediated induction of the cyclin-dependent kinase inhibitor p21WAF1/CIP1/SDI1, but the basis for the G2 arrest is unknown. Through a quantitative analysis of gene expression patterns in CRC cell lines, we have discovered that 14-3-3sigma is strongly induced by gamma irradiation and other DNA-damaging agents. The induction of 14-3-3sigma is mediated by a p53-responsive element located 1.8 kb upstream of its transcription start site. Exogenous introduction of 14-3-3sigma into cycling cells results in a G2 arrest. As the fission yeast 14-3-3 homologs rad24 and rad25 mediate similar checkpoint effects, these results document a molecular mechanism for G2/M control that is conserved throughout eukaryotic evolution and regulated in human cells by p53.
Hermeking
H
H
Johns Hopkins Oncology Center, Baltimore, Maryland, USA.
Lengauer
C
C
Polyak
K
K
He
T C
TC
Zhang
L
L
Thiagalingam
S
S
Kinzler
K W
KW
Vogelstein
B
B
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D019143:Evolution, Molecular; D005092:Exonucleases; D005095:Exoribonucleases; D016195:G2 Phase / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006131:Growth Inhibitors / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011123:Polyploidy; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007527:Isoenzymes; D009363:Neoplasm Proteins; D011506:Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D014446:Tyrosine 3-Monooxygenase; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human