A peptide fragment of azurin induces a p53-mediated cell cycle arrest in human breast cancer cells.
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.
Yamada
Tohru
T
Department of Surgical Oncology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Mehta
Rajeshwari R
RR
Lekmine
Fatima
F
Christov
Konstantin
K
King
Marissa L
ML
Majumdar
Dibyen
D
Shilkaitis
Anne
A
Green
Albert
A
Bratescu
Laura
L
Beattie
Craig W
CW
Das Gupta
Tapas K
TK
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
D018797:Cell Cycle Proteins; D016213:Cyclins; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D001400:Azurin; D046988:Proteasome Endopeptidase Complex; D001973:Bromodeoxyuridine