Related Experiment Videos
DNA damage-induced inhibition of securin expression is mediated by p53
Yunli Zhou1, Kshama R Mehta, Andrew P Choi
1Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Abstract:
Tumor suppressor p53 induces the cellular response to DNA damage mainly by regulating expression of its downstream target genes. The human securin is an anaphase inhibitor, preventing premature chromosome separation through inhibition of separase activity. It is also known as the product of the human pituitary tumor-transforming gene, pttg, a proto-oncogene. Here we report that the expression of human securin is suppressed in cells treated with the DNA-damaging drugs doxorubicin and bleomycin. This suppression requires functional p53. Analysis of the human securin promoter reveals that DNA-binding sites for Sp1 and NF-Y are both required for activation of securin expression; however, only the NF-Y site is essential for the suppression by p53. Our study indicates that securin is a p53 target gene and may play a role in p53-mediated cellular response to DNA damage.
Insights
Tumor suppressor p53 suppresses human securin expression following DNA damage. This indicates securin is a p53 target gene involved in the DNA damage response.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- The tumor suppressor p53 orchestrates cellular responses to DNA damage by regulating target gene expression.
- Human securin, also known as pituitary tumor-transforming gene (pttg), is an anaphase inhibitor and proto-oncogene.
- Securin regulates cell cycle progression by inhibiting separase activity, thus preventing premature chromosome separation.
Purpose of the Study:
- To investigate the role of human securin in the p53-mediated DNA damage response.
- To determine if securin is a direct target gene of p53.
- To elucidate the regulatory mechanism of securin expression by p53.
Main Methods:
- Treatment of cells with DNA-damaging agents (doxorubicin, bleomycin).
- Analysis of human securin expression levels.
- Functional analysis of the human securin promoter, including Sp1 and NF-Y binding sites.
- Assessment of p53 dependency for securin suppression.
Main Results:
- DNA-damaging drugs suppressed human securin expression in a p53-dependent manner.
- Analysis of the securin promoter revealed that Sp1 and NF-Y binding sites are crucial for its activation.
- Only the NF-Y binding site within the securin promoter was essential for p53-mediated suppression.
- These findings identify securin as a novel p53 target gene.
Conclusions:
- Human securin is a direct transcriptional target of the tumor suppressor p53.
- Securin plays a role in the p53-mediated cellular response to DNA damage.
- The NF-Y binding site in the securin promoter is critical for p53-mediated repression, suggesting a specific regulatory mechanism.