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Rescue of mutant p53 transcription function by ellipticine
Yanhua Peng1, Changgong Li, Lihong Chen
1Molecular Oncology Program, H Lee Moffitt Comprehensive Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Abstract:
The p53 tumor suppressor is frequently inactivated in tumors by point mutations in the DNA-binding domain, resulting in loss of sequence-specific DNA binding and transcription function. We present evidence that ellipticine can restore the transactivation function of several transfected p53 mutants (175 H, 248W, 249S, 273 H, 281G), resulting in the induction of p53-responsive genes (p21(WAF1),MDM2) and activation of a p53-responsive luciferase reporter. Ellipticine also activates mutant p53 function in tumor cells expressing endogenous 194F, 233L, 241F, and 273C mutants. Treatment with ellipticine alters mutant p53 reactivity to conformation-sensitive Pab1620 and Pab240 antibodies and increases its sequence-specific DNA-binding activity in vivo. Finally, ellipticine activates mutant p53 and induces p21(WAF1) and MDM2 expression in nude mouse tumor xenografts. These results demonstrate that ellipticine can restore transcription function to mutant p53. This property may contribute to the selectivity of ellipticine-derived compounds against tumor cell lines expressing mutant p53.
Insights
Ellipticine restores the function of mutated p53 (tumor suppressor protein) in cancer cells. This compound reactivates p53
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The p53 tumor suppressor protein is crucial for preventing cancer but is often inactivated by mutations.
- Mutations in p53's DNA-binding domain lead to loss of its tumor-suppressing functions.
Purpose of the Study:
- To investigate whether ellipticine can restore the transcriptional activity of mutant p53.
- To explore the potential of ellipticine as a therapeutic agent targeting tumors with mutant p53.
Main Methods:
- Transfection of cells with various p53 mutants.
- Assessing p53-responsive gene induction (p21WAF1, MDM2) and reporter gene activity.
- Analyzing mutant p53 conformation and DNA-binding activity in vitro and in vivo.
- Evaluating ellipticine's effect in tumor xenograft models.
Main Results:
- Ellipticine restored transactivation function to multiple p53 mutants, inducing p53-responsive genes.
- Ellipticine activated endogenous mutant p53 in tumor cells.
- Treatment altered mutant p53 conformation and enhanced its DNA-binding activity.
- Ellipticine activated mutant p53 and induced gene expression in mouse tumor xenografts.
Conclusions:
- Ellipticine effectively restores the transcription function of mutant p53.
- This reactivation of mutant p53 by ellipticine offers a potential strategy for cancer therapy.
- Ellipticine-derived compounds may exhibit selectivity against tumors with mutant p53.