AP4 encodes a c-MYC-inducible repressor of p21

Abstract

In the majority of human tumors, expression of the c-MYC oncogene becomes constitutive. Here, we report that c-MYC directly regulates the expression of AP4 via CACGTG motifs in the first intron of the AP4 gene. Induction of AP4 was required for c-MYCmediated cell cycle reentry of anti-estrogen arrested breast cancer cells and mitogen-mediated repression of the CDK inhibitor p21. AP4 directly repressed p21 by occupying four CAGCTG motifs in the p21 promoter via its basic region. AP4 levels declined after DNA damage, and ectopic AP4 interfered with p53-mediated cell cycle arrest and sensitized cells to apoptosis induced by DNA damaging agents. AP4 expression blocked induction of p21 by TGF-␤ in human keratinocytes and interfered with up-regulation of p21 and cell cycle arrest during monoblast differentiation. Notably, AP4 is specifically expressed in colonic progenitor and colorectal carcinoma cells. In conclusion, our results indicate that c-MYC employs AP4 to maintain cells in a proliferative, progenitor-like state.colorectal cancer ͉ DNA damage ͉ p53 ͉ progenitor cells ͉ TGF-beta

The Transcription Factor AP4 Promotes Oncogenic Phenotypes and Cisplatin Resistance by Regulating LAPTM4B Expression

“…It indicates that AP4 may play a dual role in cell proliferation via different pathways. Similar to our results, AP4 has been reported to promote cell growth in HCC [41], colorectal carcinoma [42] and gastric cancer [43]. Moreover, it has been proposed that AP4 could activate cell migration and EMT mediated by p53 in MDA-MB-231 cells [44] and mediate a c-MYC-induced EMT in colorectal cancer [45].…”

“…Interestingly, it has been shown that c-MYC could directly regulate AP4 expression and c-MYC-AP4-p21 cascade plays an important role in maintaining cells in a proliferative, progenitor-like state of HCC and colorectal carcinoma [41,42]. Taken together, these results suggest that c-MYC-AP4-LAPTM4B-c-MYC axis may form a feedback loop to participate in cell growth and metastasis.…”

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

“…c-Myc directly regulates the expression of AP4 via CACGTG motifs in the first intron of the AP4 gene, and AP4 directly represses p21 expression by occupying four CAGCTG motifs in the p21 promoter (Figure 6b). 37 These findings indicate that c-Myc protein downregulates p21 expression (Figure 6e). …”

Proteasome-dependent Degradation of Transcription Factor Activating Enhancer-binding Protein 4 (TFAP4) Controls Mitotic Division

“…It has been reported that TFAP4 controls the expression of numerous genes regulating cell proliferation (2,3). TFAP4 target genes also include stem cell markers such as LGR5 and regulators of epithelial-mesenchymal transition such as SNAIL and E-cadherin (2,3).…”

“…Transcription factor activating enhancer-binding protein 4 (TFAP4) 3 is a ubiquitously expressed basic helix-loop-helix leucine-zipper transcription factor that binds to the consensus E-box sequence 5Ј-CAGCTG-3Ј (1). It has been reported that TFAP4 controls the expression of numerous genes regulating cell proliferation (2,3).…”