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.

JQ1, an inhibitor of the epigenetic reader BRD4, suppresses the bidirectional MYC-AP4 axis via multiple mechanisms

“…Elevated expression of AP4 is associated with an increased metastatic capacity in colorectal cancer (6) and AP4 predicts poor prognosis in non-small cell lung cancer (25). In addition, several studies have demonstrated the critical role of AP4 in cancers and in immunology (26)(27)(28). Therefore, this study contributes to our understanding of cancer biology.…”

Regulation of activating protein-4-associated metastases of non-small cell lung cancer cells by miR-144

“…The human transcription factor activating protein-4 (AP4) is a basic helix-loop-helix leucine-zipper (bHLH-LZ) transcription factor, which forms homodimers that bind to the Ebox motif CAGCTG [10][11][12][13][14][15]. AP4 has been found to be a direct transcriptional target of c-MYC.…”

“…Upon activation, AP4 targets p21 to antagonize cell cycle arrest [15][16][17]. AP4 expression is upregulated in some cancers, e.g., breast cancer, colorectal carcinoma, and hepatocellular carcinoma [10][11][12][13][14][15]. In addition, an increase in the levels of AP4 has been reported in NSCLC, in which AP4 was found to augment epithelialmesenchymal transition (EMT) to increase NSCLC cell invasiveness [18,19].…”

Ectopic AP4 expression induces cellular senescence via activation of p53 in long-term confluent retinal pigment epithelial cells

“…AP4 was discovered to bind to the enhancer of the SV40 viral genome and activate its late transcription in vitro [49], and it attracts an increasing amount of attention because of its broad range of functions in regulating cell proliferation [13,14,17], death [15], development [18], and aging [16]. In this study, we determined that the long-term overexpression of AP4 in RPE cells ARC induced cell enlargement and flattening accompanied by cessation of cell proliferation.…”

“…Many target genes of AP4, such as insulin-like growth factor binding protein-2, caspase 9, p21, and Pin1, have recently been identified [13][14][15][16]. On the basis of the increasing number of target genes of AP4 discovered, AP4 seems to participate in several crucial physiological activities in mammalian cells, including cell proliferation [13,14,17], death [15], development [18], and aging [16]. The Hermeking group demonstrated that ectopic activation of c-MYC leads to an increase in AP4 in MCF-7 cells and determined that the AP4 gene is a direct transcriptional target of c-MYC [14].…”