Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 39, Pages 15046-15051Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0801773105
Keywords
colorectal cancer; DNA damage; p53; progenitor cells; TGF-beta
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Funding
- Ludwig Maximilians University, Munich, Germany
- Max Planck Institute of Biochemistry, Martinsried, Germany
- Ruhr University Bochum, Germany
- University of Lleida, Spain
- Karolinska Institute, Stockholm
- Helmholtz Center, Munich, Germany
- Deutsche Krebshilfe and the Max Planck Society
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In the majority of human tumors, expression of the c-MYC oncogene becomes constitutive. Here, we report that c-MYC directly regulates the expression of AP4 via CACGTG motifs in the first intron of the AP4 gene. Induction of AP4 was required for c-MYC-mediated cell cycle reentry of anti-estrogen arrested breast cancer cells and mitogen-mediated repression of the CDK inhibitor p21. AP4 directly repressed p21 by occupying four CAGCTG motifs in the p21 promoter via its basic region. AP4 levels declined after DNA damage, and ectopic AP4 interfered with p53-mediated cell cycle arrest and sensitized cells to apoptosis induced by DNA damaging agents. AP4 expression blocked induction of p21 by TGF-beta in human keratinocytes and interfered with up-regulation of p21 and cell cycle arrest during monoblast differentiation. Notably, AP4 is specifically expressed in colonic progenitor and colorectal carcinoma cells. In conclusion, our results indicate that c-MYC employs AP4 to maintain cells in a proliferative, progenitor-like state.
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