title: A peptide fragment of azurin induces a p53-mediated cell cycle arrest in human breast cancer cells.
abstract: We report that amino acids 50 to 77 of azurin (p28) preferentially enter the human breast cancer cell lines MCF-7, ZR-75-1, and T47D through a caveolin-mediated pathway. Although p28 enters p53 wild-type MCF-7 and the isogenic p53 dominant-negative MDD2 breast cancer cell lines, p28 only induces a G(2)-M-phase cell cycle arrest and apoptosis in MCF-7 cells. p28 exerts its antiproliferative activity by reducing proteasomal degradation of p53 through formation of a p28:p53 complex within a hydrophobic DNA-binding domain (amino acids 80-276), increasing p53 levels and DNA-binding activity. Subsequent elevation of the cyclin-dependent kinase inhibitors p21 and p27 reduces cyclin-dependent kinase 2 and cyclin A levels in a time-dependent manner in MCF-7 cells but not in MDD2 cells. These results suggest that p28 and similar peptides that significantly reduce proteasomal degradation of p53 by a MDM2-independent pathway(s) may provide a unique series of cytostatic and cytotoxic (apoptotic) chemotherapeutic agents.
authors.affiliation: Department of Surgical Oncology, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamada
authors.forename: Rajeshwari R
authors.initials: RR
authors.lastname: Mehta
authors.forename: Fatima
authors.initials: F
authors.lastname: Lekmine
authors.forename: Konstantin
authors.initials: K
authors.lastname: Christov
authors.forename: Marissa L
authors.initials: ML
authors.lastname: King
authors.forename: Dibyen
authors.initials: D
authors.lastname: Majumdar
authors.forename: Anne
authors.initials: A
authors.lastname: Shilkaitis
authors.forename: Albert
authors.initials: A
authors.lastname: Green
authors.forename: Laura
authors.initials: L
authors.lastname: Bratescu
authors.forename: Craig W
authors.initials: CW
authors.lastname: Beattie
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Das Gupta
mesh_terms: D000818:Animals; D001400:Azurin / Q000737:chemistry*; D001943:Breast Neoplasms / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016213:Cyclins / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D016213:Cyclins; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D001400:Azurin; D046988:Proteasome Endopeptidase Complex; D001973:Bromodeoxyuridine