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p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor.
- Source :
-
Oncogene [Oncogene] 2001 Sep 13; Vol. 20 (41), pp. 5818-25. - Publication Year :
- 2001
-
Abstract
- 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.
- Subjects :
- CDC2 Protein Kinase genetics
CDC2 Protein Kinase metabolism
Cell Division genetics
Cellular Senescence physiology
Cyclin B genetics
Cyclin B metabolism
DNA-Binding Proteins genetics
Gene Silencing
Genes, Tumor Suppressor
Humans
Nuclear Proteins genetics
Phosphoproteins genetics
Trans-Activators genetics
Transcription, Genetic
Tumor Cells, Cultured
Tumor Protein p73
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Proteins
CCAAT-Binding Factor genetics
Cellular Senescence genetics
DNA-Binding Proteins physiology
Membrane Proteins
Nuclear Proteins physiology
Phosphoproteins physiology
Trans-Activators physiology
Transcription Factors genetics
Tumor Suppressor Protein p53 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 20
- Issue :
- 41
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 11593387
- Full Text :
- https://doi.org/10.1038/sj.onc.1204748