Transcription Factor AP4 Mediates Cell Fate Decisions: To Divide, Age, or Die

Abstract

Activating Enhancer-Binding Protein 4 (AP4)/transcription factor 4 (TFAP4) is a basic-helix-loop-helix-leucine-zipper transcription factor that was first identified as a protein bound to SV40 promoters more than 30 years ago. Almost 15 years later, AP4 was characterized as a target of the c-Myc transcription factor, which is the product of a prototypic oncogene that is activated in the majority of tumors. Interestingly, AP4 seems to represent a central hub downstream of c-Myc and N-Myc that mediates some of their functions, such as proliferation and epithelial-mesenchymal transition (EMT). Elevated AP4 expression is associated with progression of cancer and poor patient prognosis in multiple tumor types. Deletion of AP4 in mice points to roles of AP4 in the control of stemness, tumor initiation and adaptive immunity. Interestingly, ex vivo AP4 inactivation results in increased DNA damage, senescence, and apoptosis, which may be caused by defective cell cycle progression. Here, we will summarize the roles of AP4 as a transcriptional repressor and activator of target genes and the contribution of protein and non-coding RNAs encoded by these genes, in regulating the above mentioned processes. In addition, proteins interacting with or regulating AP4 and the cellular signaling pathways altered after AP4 dysregulation in tumor cells will be discussed.

Integrative analysis allows a global and precise identification of functional miRNA target genes in mESCs

“…Finally, to better understand the role of TFAP4 in mESCs gene regulation, we performed a gene ontology analysis using the ClueGO tool on the 121 genes (Bindea et al, 2009). Most of the groups identified by the analysis, including "regulation of cell growth", "regulation of WNT signaling pathway", "regulation of cellular response to growth factor stimulus", "nephron development" (Figure 4E, Table S7) are in line with previous reports of TFAP4 being an important regulator involved in developmental processes (Wong et al, 2021). In conclusion, our data demonstrate a major role for TFAP4 in stem cell gene regulation and as a TF in mouse early development.…”

“…Moreover, gene ontology analysis reveals important roles for TFAP4 in mouse early development, cell growth roles as well as in the Wnt/β-catenin pathway. In humans, Tfap4 has been previously described to regulate stemness and proliferation (Jackstadt et al, 2013;Jung et al, 2008), but especially to drive cancer malignancy (for review (Wong et al, 2021)).…”

Deriving time-concordant event cascades from gene expression data: A case study for Drug-Induced Liver Injury (DILI)

“…|logFC|, the enrichment p-value, and the TPR before or at adverse histopathology. These are shown in Fig 7 and summarised in S4 Table . The next most significantly enriched pathway-level event after decreased bile acid and salt recycling was the down-regulation of glycosaminoglycan metabolism and the most significantly enriched TF-level event was the down-regulation of Transcription factor activating enhancer binding protein 4 (Tfap4) which shows emerging roles in cell fate decisions [35]. Among the up-regulated events, the most significant enrichment is found for cell cycle checkpoints and DNA repair among the pathway-level events as well as E2F Transcription Factor 2 (E2f2), which controls cellular proliferation and liver regeneration [36], among the TF-level events.…”

From Channels to Canonical Wnt Signaling: A Pathological Perspective

“…For example, the cyclin D1 ( CCND1 ) and the protoncogene myc ( MYC ) are up-regulated by β-catenin, thus inducing G1 to the S phase cell cycle transition. Since this last step is characterized by DNA replication, it ultimately leads to mitosis and cell proliferation [ 32 , 33 ].…”