CDC20, a potential cancer therapeutic target, is negatively regulated by p53.
The p53 protein inhibits malignant transformation through direct and indirect regulation of transcription of many genes related to cell cycle, apoptosis and cellular senescence. A number of genes induced by p53 have been well characterized, but biological significance of genes whose expression was suppressed by p53 is still largely undisclosed. To clarify the roles of p53-suppressive genes in carcinogenesis, we analysed two data sets of whole-genome expression profiles, one for cells in which wild-type p53 was exogenously introduced and the other for a large number of clinical cancer tissues. Here, we identified CDC20 that was frequently upregulated in many types of malignancies and remarkably suppressed by ectopic introduction of p53. CDC20 expression was suppressed by genotoxic stresses in p53- and p21-dependent manners through CDE-CHR elements in the CDC20 promoter. Furthermore, small interference RNA (siRNA)-mediated silencing of p53 induced CDC20 expression in normal human dermal fibroblast cells. As we expected, treatment of cancer cells with siRNA against CDC20 induced G(2)/M arrest and suppressed cell growth. Our results indicate that p53 inhibits tumor cell growth through the indirect regulation of CDC20 and that CDC20 might be a good potential therapeutic target for a broad spectrum of human cancer.
Kidokoro
T
T
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Tanikawa
C
C
Furukawa
Y
Y
Katagiri
T
T
Nakamura
Y
Y
Matsuda
K
K
D017209:Apoptosis; D015153:Blotting, Western; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D003114:Colony-Forming Units Assay; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016195:G2 Phase / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; C577488:CDC20 protein, human; D008156:Luciferases