| Summary: | Here we analyzed the function of the c-MYC-inducible basic helix–loop–helix leucine-zipper transcription factor AP4 in AP4-deficient mouse embryo fibroblasts (MEFs). Loss of AP4 resulted in premature senescence and resistance towards immortalization. Senescence was accompanied by induction of the cyclin-dependent kinase inhibitor-encoding genes p16, a known tumor suppressor, and p21, a previously described target for repression by AP4. Notably, AP4 directly repressed p16 expression via conserved E-box motifs in MEFs and human diploid fibroblasts. Senescence caused by AP4-deficiency was prevented by depletion of p16 and/or p21, demonstrating that these factors mediate senescence caused by AP4 loss. As senescence induced by the loss of AP4 was rescued by ectopic AP4, secondary lesions were not involved in causing premature senescence. Activation of c-MYC resulted in repression of p21 and p16 in AP4+/+, but not in AP4−/− MEFs. Furthermore, after combined expression of c-MYC and mutant RAS in MEFs, AP4 was required for colony formation, anchorage-independent growth and tumor formation in mice. In addition, combined ectopic expression of AP4 and mutant RAS in MEFs resulted in colony formation. However, additional loss of the p53 tumor suppressor was necessary for anchorage-independent growth and tumor formation of MEFs by combined AP4 and mutant RAS expression. In conclusion, this study identified AP4 as an oncogenic antagonist of cellular senescence. AP4 achieves this effect by direct repression of p16 and p21, and may thereby critically contribute to c-MYC function and tumor progression.
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