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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Generation of p53 suppressor peptide from the fragment of p53 protein
1Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
Abstract:
The p53 protein, encoded by a tumor suppressor gene, mediates growth arrest or apoptosis in response to a variety of stresses. p53-dependent apoptosis, occurring in several sensitive tissues after radiation or chemotherapy, is partially responsible for the side effects of cancer treatment, making p53 a potential target for therapeutic suppression. p53 function can be suppressed by the ectopic expression of p53-derived peptides, isolated earlier using functional selection of genetic suppressor elements (GSEs) from a library of randomly fragmented p53 cDNA (Ossovskaya et al. [1996]. Proc. Natl. Acad. Sci. U.S.A. 93, 10309). The potent p53-suppressing GSE, GSE56, had been used to generate in an E. coli expression system a peptide with anti-p53 activity by fusion of the GSE-encoded sequence with penetratin, a 16-amino-acid-long peptide capable of efficient translocation through cell membranes. Fusion with penetratin does not affect the anti-p53 activity of retrovirus-transduced GSE56. The fused peptide was able to attenuate p53-mediated transactivation and apoptosis when added into culture media. Interestingly, GSE56-derived peptide with no penetratin also had accumulated in the cells and showed similar, though lower, anti-p53 activity. This study provides the rationale and methodological basis for efficient generation of biologically active peptides with therapeutic potential from GSEs isolated through functional selection.
Insights
Therapeutic peptides targeting the tumor suppressor p53 (a protein mediating apoptosis) were generated using genetic suppressor elements (GSEs). These peptides show potential for cancer treatment by suppressing p53-mediated apoptosis and reducing side effects.
Area of Science:
- Molecular Biology
- Cancer Therapeutics
- Protein Engineering
Background:
- The p53 protein, a tumor suppressor, induces apoptosis in response to cellular stress.
- p53-mediated apoptosis contributes to side effects of cancer treatments like radiation and chemotherapy.
- Targeting p53 offers a strategy for improving cancer therapy and mitigating adverse effects.
Purpose of the Study:
- To develop biologically active peptides for suppressing p53 function.
- To establish a method for generating therapeutic peptides from genetic suppressor elements (GSEs).
- To evaluate the anti-p53 activity of engineered peptides.
Main Methods:
- Functional selection was used to isolate p53-suppressing GSEs from a cDNA library.
- A potent GSE (GSE56) was engineered into a fusion peptide with penetratin for cell membrane translocation.
- Peptide activity was assessed by measuring attenuation of p53-mediated transactivation and apoptosis in cell culture.
Main Results:
- A fusion peptide of GSE56 and penetratin demonstrated potent anti-p53 activity, reducing p53-mediated apoptosis.
- The penetratin moiety facilitated efficient cell membrane translocation without compromising anti-p53 activity.
- A GSE56-derived peptide without penetratin also exhibited anti-p53 activity intracellularly, though at a lower level.
Conclusions:
- This study validates a method for generating therapeutic peptides with anti-p53 activity from GSEs.
- Engineered peptides, particularly the GSE56-penetratin fusion, show promise for targeted p53 suppression in cancer therapy.
- The findings provide a foundation for developing novel peptide-based therapeutics to modulate p53 function.
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