Rescue of mutant p53 transcription function by ellipticine.
The p53 tumor suppressor is frequently inactivated in tumors by point mutations in the DNA-binding domain, resulting in loss of sequence-specific DNA binding and transcription function. We present evidence that ellipticine can restore the transactivation function of several transfected p53 mutants (175 H, 248W, 249S, 273 H, 281G), resulting in the induction of p53-responsive genes (p21(WAF1),MDM2) and activation of a p53-responsive luciferase reporter. Ellipticine also activates mutant p53 function in tumor cells expressing endogenous 194F, 233L, 241F, and 273C mutants. Treatment with ellipticine alters mutant p53 reactivity to conformation-sensitive Pab1620 and Pab240 antibodies and increases its sequence-specific DNA-binding activity in vivo. Finally, ellipticine activates mutant p53 and induces p21(WAF1) and MDM2 expression in nude mouse tumor xenografts. These results demonstrate that ellipticine can restore transcription function to mutant p53. This property may contribute to the selectivity of ellipticine-derived compounds against tumor cell lines expressing mutant p53.
Peng
Yanhua
Y
Molecular Oncology Program, H Lee Moffitt Comprehensive Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Li
Changgong
C
Chen
Lihong
L
Sebti
Said
S
Chen
Jiandong
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004611:Ellipticines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009687:Nuclear Proteins; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004611:Ellipticines; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C034192:ellipticine; D004247:DNA; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2