Abstract
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.
Highlights
The AP4 protein belongs to the group of basichelix-loop-helix leucine zipper transcription factors [1]
Thereby we found that AP4 represents an epithelial-mesenchymal transition (EMT) inducing transcription factor (EMT-TF)
In order to determine the function of AP4 during cell cycle progression we analyzed mouse embryonic fibroblasts (MEFs) derived from AP4 knock-out mice, which we had generated by deletion of AP4 exons 2–4 [10]
Summary
The AP4 protein belongs to the group of basichelix-loop-helix leucine zipper (bHLH-LZ) transcription factors [1]. We previously identified the AP4 gene as a direct transcriptional target of c-MYC and showed that the gene encoding the CDK-inhibitor p21 is directly repressed by AP4 in human cells [8, 9]. In order to determine the function of AP4 during cell cycle progression, we analyzed AP4-deficient MEFs. Our results imply that AP4 is, at least in MEFs, a required mediator of cell cycle progression after mitogenic stimulation and c-MYC activation. Our results imply that AP4 is, at least in MEFs, a required mediator of cell cycle progression after mitogenic stimulation and c-MYC activation This function of AP4 is at least in part mediated by direct induction of the central cell cycle regulator CDK2. Our analyses further revealed that AP4 function is required for successful completion of the final steps of cell divisions, as AP4-deficient cells display a cytokinesis defect resulting in tetraploid cells
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