Priority Research Papers:
AP4 is required for mitogen- and c-MYC-induced cell cycle progression
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1 Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, D-80337 Munich, Germany
2 German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany
3 German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany
Prof. Heiko Hermeking, e-mail: firstname.lastname@example.org
Keywords: AP4, AP-4, TFAP4, c-MYC, cell cycle, cytokinesis
Received: August 8, 2014 Revised and Accepted: August 11, 2014 Published: August 19, 2014
AP4 represents a c-MYC-inducible bHLH-LZ transcription factor, which displays elevated expression in many types of tumors. We found that serum-starved AP4-deficient mouse embryo fibroblasts (MEFs) were unable to resume proliferation and showed a delayed S-phase entry after restimulation. Furthermore, they accumulated as tetraploid cells due to a cytokinesis defect. In addition, AP4 was required for c-MYC-induced cell cycle re-entry. AP4-deficient MEFs displayed decreased expression of CDK2 (cyclin-dependent kinase 2), which we characterized as a conserved and direct AP4 target. Activation of an AP4 estrogen receptor fusion protein (AP4-ER) enhanced proliferation of human diploid fibroblasts in a CDK2-dependent manner. However, in contrast to c-MYC-ER, AP4-ER activation was not sufficient to induce cell cycle re-entry or apoptosis in serum-starved MEFs. AP4-deficiency was accompanied by increased spontaneous and c-MYC-induced DNA damage in MEFs. Furthermore, c-MYC-induced apoptosis was decreased in AP4-deficient MEFs, suggesting that induction of apoptosis by c-MYC is linked to its ability to activate AP4 and thereby cell cycle progression. Taken together, these results indicate that AP4 is a central mediator and coordinator of cell cycle progression in response to mitogenic signals and c-MYC activation. Therefore, inhibition of AP4 function may represent a therapeutic approach to block tumor cell proliferation.
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