MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53.
We have previously identified the p53-reactivating compound RITA in a cell-based screen. Here, using microarray analysis, we show that the global transcriptional response of tumor cells to RITA is p53 dependent. Pathway analysis revealed induction of the p53 apoptosis pathway, consistent with apoptosis being the major response to RITA in cancer cells. We uncovered that MDM2 released from p53 by RITA promotes degradation of p21 and the p53 cofactor hnRNP K, required for p21 transcription. Functional studies revealed MDM2-dependent inhibition of p21 as a key switch regulating cell fate decisions upon p53 reactivation. Our results emphasize the utility of targeting wild-type p53 protein itself as a promising approach for anticancer therapy.
Enge
Martin
M
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Bao
Wenjie
W
Hedström
Elisabeth
E
Jackson
Stephen P
SP
Moumen
Abdeladim
A
Selivanova
Galina
G
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D009363:Neoplasm Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; C403666:ZNF331 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2