title: Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides.
abstract: The p53 tumor suppressor serves as a major barrier against malignant transformation. Over 50% of tumors inactivate p53 by point mutations in its DNA binding domain. Most mutations destabilize p53 protein folding, causing its partial denaturation at physiological temperature. Thus a high proportion of human tumors overexpress a potential potent tumor suppressor in a non-functional, misfolded form. The equilibrium between the properly folded and misfolded states of p53 may be affected by molecules that interact with p53, stabilizing its native folding and restoring wild type p53 activity to cancer cells. To select for mutant p53 (mutp53) reactivating peptides, we adopted the phage display technology, allowing interactions between mutp53 and random peptide libraries presented on phages and enriching for phage that favor the correctly folded p53 conformation. We obtained a large database of potential reactivating peptides. Lead peptides were synthesized and analyzed for their ability to restore proper p53 folding and activity. Remarkably, many enriched peptides corresponded to known p53-binding proteins, including RAD9. Importantly, lead peptides elicited dramatic regression of aggressive tumors in mouse xenograft models. Such peptides might serve as novel agents for human cancer therapy.
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Perry
authors.initials: P
authors.lastname: Tal
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Eizenberger
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Cohen
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Naomi
authors.initials: N
authors.lastname: Goldfinger
authors.affiliation: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Pietrokovski
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Varda
authors.initials: V
authors.lastname: Rotter
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D050505:Mutant Proteins; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53
keywords: conformation; p53; peptides; pre-clinical; reactivation