A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines.
The hdm2 protein negatively regulates p53 tumour suppressor activity. Upon binding to p53, hdm2 stimulates p53 degradation and inhibits its transcriptional activity. Moreover, the hdm2 protein is overexpressed in various tumours inactivating p53. We report here that an octamer synthetic peptide derived from p53 inhibits the p53-hdm2 interaction in vitro. In cellular assays, this untagged peptide penetrates tumour cells and induces the accumulation of p53. The accumulation of p53 leads to its activation. Two gene products transcriptionally regulated by p53, p21Waf1/Cip1 and hdm2, are induced in the presence of the peptide. When used with tumour cells that overexpress hdm2, the peptide induces the death of these tumour cells by apoptosis. The mode of action of this peptide differs from that of DNA-damaging agents (e.g. cisplatin) in that it does not induce p53 phosphorylation on serine 15. This work validates with a low molecular mass molecule our current knowledge on the regulation of the p53 pathway by the hdm2 protein. It also shows that inhibitors of the p53-hdm2 interaction are very attractive candidates for the activation of the p53 pathway in tumours expressing wild-type p53.
Chène
P
P
Novartis, Oncology Department, Basel, Switzerland. patrick_chene@yahoo.com
Fuchs
J
J
Bohn
J
J
García-Echeverría
C
C
Furet
P
P
Fabbro
D
D
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C493956:CDKN1A protein, human; D061945:Caspase Inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D012694:Serine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin