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c‐Myc represses FOXO3a‐mediated transcription of the gene encoding the p27 Kip1 cyclin dependent kinase inhibitor
Author(s) -
Chandramohan Vidyalakshmi,
Mineva Nora D.,
Burke Brian,
Jeay Sébastien,
Wu Min,
Shen Jian,
Yang William,
Hann Stephen R.,
Sonenshein Gail E.
Publication year - 2008
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21765
Subject(s) - chromatin immunoprecipitation , microbiology and biotechnology , ectopic expression , biology , cancer research , cell growth , transcription factor , promoter , gene expression , chemistry , gene , biochemistry , genetics
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. J. Cell. Biochem. 104: 2091–2106, 2008. © 2008 Wiley‐Liss, Inc.