c-Myc represses FOXO3a-mediated transcription of the gene encoding the p27(Kip1) cyclin dependent kinase inhibitor.

Chandramohan V, Mineva ND, Burke B, Jeay S, Wu M, Shen J, Yang W, Hann SR, Sonenshein GE
J Cell Biochem. 2008 104 (6): 2091-106

PMID: 18393360 · DOI:10.1002/jcb.21765

The p27(Kip1) (p27) cyclin-dependent kinase inhibitor and c-Myc oncoprotein play essential roles in control of cell cycle progression and apoptosis. Induction of p27 (CDKN1B) gene transcription by Forkhead box O proteins such as FOXO3a leads to growth arrest and apoptosis. Previously, we observed that B cell receptor (surface IgM) engagement of WEHI 231 immature B lymphoma cells with an anti-IgM antibody results in activation of FOXO3a, growth arrest and apoptosis. As ectopic c-Myc expression in these cells prevented anti-IgM induction of p27 and cell death, we hypothesized that c-Myc represses FOXO3a-mediated transcription. Here we show that c-Myc inhibits FOXO3a-mediated activation of the p27 promoter in multiple cell lines. The mechanism of this repression was explored using a combination of co-immunoprecipitation, oligonucleotide precipitation, and chromatin immunoprecipitation experiments. The studies demonstrate a functional association of FOXO3a and c-Myc on a proximal Forkhead binding element in the p27 promoter. This association involves the Myc box II domain of c-Myc and the N-terminal DNA-binding portion of FOXO3a. Analysis of publicly available microarray datasets showed an inverse pattern of c-MYC and p27 RNA expression in primary acute myeloid leukemia, prostate cancer and tongue squamous cell carcinoma samples. The inhibition of FOXO3a-mediated activation of the p27 gene by the high aberrant expression of c-Myc in many tumor cells likely contributes to their uncontrolled proliferation and invasive phenotype.

MeSH Terms (18)

Animals Apoptosis Binding Sites Cell Line Cyclin-Dependent Kinase Inhibitor p27 Forkhead Box Protein O3 Forkhead Transcription Factors Gene Expression Regulation, Neoplastic Humans Mice Neoplasms Promoter Regions, Genetic Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins c-myc Repressor Proteins RNA, Messenger Transcription, Genetic

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