Conformational and molecular basis for induction of apoptosis by a p53 C-terminal peptide in human cancer cells.
A p53-derived C-terminal peptide induced rapid apoptosis in breast cancer cell lines carrying endogenous p53 mutations or overexpressed wild-type (wt) p53 but was not toxic to nonmalignant human cell lines containing wt p53. Apoptosis occurred through a Fas/APO-1 signaling pathway involving increased extracellular levels of Fas/FasL in the absence of protein synthesis, as well as activation of a Fas/APO-1-specific protease, FLICE. The peptide activity was p53-dependent, and it had no effect in three tumor cell lines with null p53. Furthermore, the C-terminal peptide bound to p53 protein in cell extracts. Thus, p53-dependent, Fas/APO-1 mediated apoptosis can be induced in breast cancer cells with mutant p53 similar to the recently described Fas/APO-1 induced apoptosis by wt p53. However, mutant p53 without p53 peptide does not induce a Fas/APO-1 activation or apoptosis. Docking of the computed low energy conformations for the C-terminal peptide with those for a recently defined proline-rich regulatory region from the N-terminal domain of p53 suggests a unique low energy complex between the two peptide domains. The selective and rapid induction of apoptosis in cancer cells carrying p53 abnormalities may lead to a novel therapeutic modality.
Kim
A L
AL
College of Physicians, Surgeons of Columbia University, Experimental Therapeutics Program, Division of Medical Oncology, New York, New York 10032, USA.
Raffo
A J
AJ
Brandt-Rauf
P W
PW
Pincus
M R
MR
Monaco
R
R
Abarzua
P
P
Fine
R L
RL
D000595:Amino Acid Sequence; D017209:Apoptosis; D015153:Blotting, Western; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D004247:DNA / Q000378:metabolism; D053222:Fas Ligand Protein; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005434:Flow Cytometry; D005801:Genes, Homeobox; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D010455:Peptides; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D004247:DNA; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases