%0 Journal Article
%A Jackstadt, Rene-Filip
%A Hermeking, Heiko
%T AP4 is required for mitogen- and c-MYC-induced cell cycle progression.
%J OncoTarget
%V 5
%N 17
%@ 1949-2553
%C [S.l.]
%I Impact Journals LLC
%M DKFZ-2017-02111
%P 7316 - 7327
%D 2014
%X 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.
%K Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (NLM Chemicals)
%K Mitogens (NLM Chemicals)
%K Proto-Oncogene Proteins c-myc (NLM Chemicals)
%K REPIN1 protein, human (NLM Chemicals)
%K Transcription Factors (NLM Chemicals)
%K transcription factor AP4, mouse (NLM Chemicals)
%K Cyclin-Dependent Kinase 2 (NLM Chemicals)
%9 Journal Article
%$ pmid:25261373
%2 pmc:PMC4202125
%R 10.18632/oncotarget.2348
%U https://inrepo02.dkfz.de/record/125996