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Transcriptional Regulation of Mitotic Checkpoint Gene MAD1 by p53
- Source :
- Journal of Biological Chemistry. 278:37439-37450
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
Abstract
- p53 regulates a number of genes through transcriptional activation and repression. p53-dependent mitotic checkpoint has been described, but the underlying mechanism is still obscure. Here we examined the effect of p53 on the expression of a human mitotic checkpoint protein, Mitosis Arrest Deficiency 1 (MAD1), in cultured human cells. The expression of MAD1 was reduced when the cells were overexpressing exogenously introduced wild-type p53. The same reduction was also observed when the cells were treated with anticancer agents 5-fluorouracil and cisplatin or were irradiated with UV. Consistently, MAD1 promoter activity diminished in a dose-dependent manner when induced by p53, indicating that p53 repressed MAD1 at a transcriptional level. Intriguingly, several tumor hot spot mutations in p53 (V143A, R175H, R248W, and R273H) did not abolish the ability of p53 to repress MAD1 expression. By serial truncation of the MAD1 promoter, we confined the p53-responsive element to a 38-bp region that represents a novel sequence distinct from the known p53 consensus binding site. Trichostatin A, a histone deacetylase inhibitor, relieved the p53 transrepression activity on MAD1. Chromatin immunoprecipitation assay revealed that p53, histone deacetylase 1, and co-repressor mSin3a associated with the MAD1 promoter in vivo. Taken together, our findings suggest a regulatory mechanism for the mitotic checkpoint in which MAD1 is inhibited by p53.
- Subjects :
- Transcription, Genetic
Mad1
medicine.drug_class
Molecular Sequence Data
Cell Cycle Proteins
Histone Deacetylase 1
Biology
Hydroxamic Acids
Response Elements
Biochemistry
Histone Deacetylases
Cell Line, Tumor
Basic Helix-Loop-Helix Transcription Factors
medicine
Transcriptional regulation
Humans
Promoter Regions, Genetic
Molecular Biology
Mitosis
Regulation of gene expression
Base Sequence
Histone deacetylase inhibitor
Nuclear Proteins
Cell Biology
G2-M DNA damage checkpoint
Phosphoproteins
Genes, cdc
Repressor Proteins
Trichostatin A
Gene Expression Regulation
Cancer research
Tumor Suppressor Protein p53
Chromatin immunoprecipitation
Transcription Factors
medicine.drug
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 278
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....9844b9d9baca2a6a11b78b0476bc057a