p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor.
Recent studies have identified two p53 homologues, p63 and p73. They activate p53-responsive promoters and induce apoptosis when overexpressed in certain human tumors. Here, we report that p63, like p53 and p73, induces replicative senescence when expressed in a tetracycline-regulated manner in EJ cells lacking a functional p53. In addition to transcription activation of p53-responsive genes, we found that p63 and p73 repress transcription of the cdk1 and cyclin B genes, both of which are irreversibly repressed in senescent human fibroblast. In transient transfection assay, p63 and p73 repress the cdk1 promoter regardless of the presence of a dominant negative mutant form of p53. Furthermore, we found that DNA binding activity of NF-Y transcription factor, which is essential for transcription of the cdk1 and cyclin B genes and inactivated in senescent fibroblast, is significantly decreased by expression of either of p53, p63, or p73. Since NF-Y binds to many promoters besides the cdk1 and cyclin B promoters, inactivation of NF-Y by p53 family genes may be a general mechanism for transcription repression in replicative senescence.
Jung
M S
MS
National Research Laboratory for Cell Cycle Regulation, Department of Microbiology, Dankook University College of Medicine, Chonan, 330-714, Korea.
Yun
J
J
Chae
H D
HD
Kim
J M
JM
Kim
S C
SC
Choi
T S
TS
Shin
D Y
DY
D023081:CCAAT-Binding Factor / Q000235:genetics*; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008565:Membrane Proteins; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D023081:CCAAT-Binding Factor; C081876:CKAP4 protein, human; D019926:Cyclin B; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C402244:nuclear factor Y; D016203:CDC2 Protein Kinase