title: AP4 is required for mitogen- and c-MYC-induced cell cycle progression.
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.
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, D-80337 Munich, Germany.
authors.forename: Rene
authors.initials: R
authors.lastname: Jackstadt
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, D-80337 Munich, Germany. German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany. German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008934:Mitogens / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D008934:Mitogens; D016271:Proto-Oncogene Proteins c-myc; C404766:REPIN1 protein, human; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C562117:transcription factor AP4, mouse; D051357:Cyclin-Dependent Kinase 2