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p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis
S Okamura1, H Arakawa, T Tanaka
1Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan.
Molecular Cell
|August 21, 2001
Summary
p53DINP1 is a novel gene that regulates p53-dependent apoptosis. Inhibiting p53DINP1 blocks DNA damage-induced cell death, while its overexpression enhances apoptosis via p53 Ser46 phosphorylation.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The tumor suppressor protein p53 plays a critical role in cellular responses to DNA damage.
- p53 activity is tightly regulated, involving post-translational modifications like phosphorylation.
- Understanding novel regulators of p53 function is crucial for cancer therapy.
Purpose of the Study:
- To identify novel genes induced by p53.
- To investigate the role of a newly identified gene, p53DINP1, in p53-dependent apoptosis.
- To elucidate the mechanism by which p53DINP1 influences p53 activity.
Main Methods:
- Differential display technique to identify p53-inducible genes.
- Utilized a cell line with a controlled expression system for wild-type p53.
- Employed antisense oligonucleotides to inhibit p53DINP1 expression.
- Investigated the effects of p53DINP1 overexpression and DNA damage (DSBs) on apoptosis and p53 phosphorylation.
Main Results:
- Isolated and identified p53DINP1 (p53-dependent damage-inducible nuclear protein 1).
- Inhibition of p53DINP1 blocked DNA double-strand break (DSB)-induced cell death, p53 Ser46 phosphorylation, and p53AIP1 induction.
- Overexpression of p53DINP1 synergistically enhanced DSB-induced apoptosis, p53 Ser46 phosphorylation, and p53AIP1 expression.
- Identified a protein complex interacting with p53DINP1 that phosphorylates p53 at Ser46.
Conclusions:
- p53DINP1 is a key regulator of p53-dependent apoptosis.
- p53DINP1 functions by promoting p53 phosphorylation at Serine 46.
- p53DINP1 acts as a cofactor for the p53-Ser46 kinase, mediating apoptotic responses to DNA damage.
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