Transcriptional activator factor AP2 (TFAP2) is a sequence DNA-binding transcription factor. This transcription factor is critical for many aspects of life such as gene regulation during development, cell differentiation and environmental signals. TFAP2 drives or suppresses the expression of target genes through signal transduction, and is a regulatory force in the proliferation, differentiation, invasion and metastasis of tumour cells. TFAP2 binds to DNA sequences in the promoter region of target genes and controls gene expression's activation or deactivation.
TFAP2 is responsible for adhesion, migration and differentiation of cells, and for embryonic development including the neural crest and organs. Expression of TFAP2 is abnormal in all types of cancers, and it also functions as an oncogene or tumor suppressor that promotes tumour growth and metastasis. TFAP2 is modulable via a variety of signalling pathways so it can detect extracellular signals and modulate gene expression. TFAP2 is a functional transcription factor with functions in development, cancer biology and cell-response.
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Related Diseases
The functions of TFAP2 vary for different cancers. It can, for instance, be tumour suppressor in some tumor cells and growth and dissemination in others. It's this that makes TFAP2 a target for cancer research. pLV-EGFP(2A)puro-TFAP2 plasmid and stable cell line were made and overexpression of TFAP2 induced growth of renal clear cell carcinoma cells. TFAP2 was also an independent predictive factor for good response and survival in patients with late-stage bladder cancer who received cisplatin-based chemotherapy.
TFAP2 mutations can also bring about some genetic disorders. For instance, the gene's mutations were linked to defects in facial development including TAP2-associated facial dysmorphic syndrome (B branchial cleft facial syndrome or BOFS). BOFS is defined as growth retardation, bilateral branchial sinus deformities with hemangiomas, blisters, cleft lip (with or without cleft palate), pseudocleft upper lip, nasolacrimal duct obstruction, low-set ears (posterior rotation), malformations, asymmetric nose (wide bridge, flat tip), conductive/nervous hearing loss, ocular and renal abnormalities.
Because TFAP2 is involved in so many processes in the biological world, comprehensive studies can give us new ideas for cures.
Fig. 1 Immunohistochemical interaction staining study of bladder cancer tissue with TFAP2α antibody (Nordentoft, I.; et al.2011).
Physiological Activities and Functions
TFAP2α can bind specifically to DNA and plays a vital role in various biological processes. TFAP2α is involved in regulating normal cell proliferation, differentiation and embryonic development, and can turn on, off, enhance or weaken the expression of multiple target genes by regulating signal transduction, playing an important regulatory role in the proliferation, differentiation, invasion and metastasis of tumor cells. TFAP2α can promote the formation of transcription complexes that regulate gene expression with multiple transcription factors and co-regulators. The study of TFAP2α helps to understand developmental disorders, cancer progression, and may find therapeutic targets in diseases with TFAP2α dysregulation. TFAP2α binds to the consensus sequence 5'-GCCNNNGGC-3' and activates genes involved in a large number of important biological functions, including proper eye, face, body wall, limb and neural tube development. TFAP2α may inhibit many genes including MCAM/MUC18, C/EBPα and MYC. TFAP2α is the only AP-2 protein required for the early morphogenesis of lens vesicles. Together with CITED2 coactivator, it stimulates transcriptional activation of PITX2 P1 promoter. The physiological activities of TFAP2α mainly include:
- Gene regulation
- Developmental role
- Signal transduction
- Interaction
TFAP2α Expression in Tumors
TFAP2 appears in different expression profiles and is used in different cancers. Overexpression of TFAP2, for instance, might drive the growth and spread of tumour cells in some cancers, but it might also be suppressive in other types of cancer. Expression of TFAP2 could be related to patient outcome. In fact, research has found low TFAP2 expression in some tumours predictive of poor outcomes.
Breast cancer
We have even discovered that low TFAP2 levels in the nucleus and/or protein translocation to the cytoplasm could lead to shorter nonrecurrence-free and breast cancer-free survival. Low levels of nuclear TFAP2 in patients with positive lymph nodes are associated with disease progression and metastasis. TFAP2 loss also predicts a greater likelihood of recurrence of breast cancer.
Melanoma
We know from human melanoma studies that greater TFAP2 expression in the cytoplasm compared with the nucleus is predictive of poor prognosis. Lack of nuclear TFAP2 expression correlates with malignant transformation and melanoma progression, so perhaps TFAP2 transfer from the cytoplasm to the nucleus was also disrupted during the development of melanoma. So the main defect in TFAP2 function in metastatic melanoma looks like nuclear translocation loss. This might be because of changes to the nuclear pore complex or in the activity of transport receptors (karyopherins/importins/exportins) or even in the TFAP2 protein itself.
Bladder Cancer
Reduced TFAP2 transcription/translation or more turnover are the more likely causes of bladder cancer than translocation. Higher nuclear and cytoplasmic TFAP2 protein indicates better overall and progression-free survival. TFAP2 knockdown slowed SW780 bladder cells' proliferation and lowered cisplatin- and gemcitabine-induced cell death.
Renal Clear Cell Carcinoma
TFAP2 overexpression can greatly decrease proliferation of the renal clear cell carcinoma cell lines 786-O and Caki-2 cells, cell cycle modifications, and dramatically increase the amount of cells that remain in the G0/G1 phase, and dramatically reduce the number of cells remaining in the S phase, thus resulting in G1/S phase arrest and thus cell death.
TFAP2α Affects Cell Proliferation
TFAP2 (transcription factor AP-2) regulates proliferation, differentiation and survival of cells. It's a transcription factor involved in the expression of various genes and is tightly connected to cell cycle, proliferation and apoptosis. The TFAP2 controls gene expression for cell cycle genes by attaching to gene promoters and thus controlling cell growth. It could, for instance, increase the expression of some genes for cell-proliferation and decrease the expression of genes that inhibit cell-proliferation.
Conclusion
TFAP2 is a transcription factor from the TFAP2 family. It is infamous for its role in gene regulation, and for controlling how cells respond to external and internal stimuli. The biological role of TFAP2 has very little to do with its function as a regulator of gene expression. TFAP2, by binding to DNA sequences, controls transcription of target genes at crucial cellular loci. TFAP2 has become a marker for chemosensitivity in bladder cancer and the more TFAP2 is expressed, the better the response to cisplatin.
TFAP2 regulates a specific function that could be a target for therapy in particular in tumor cells. The activity of TFAP2 or its target genes can be tuned, which in turn allows new anti-tumor interventions. TFAP2 is involved in multiple signalling pathways including the PI3K/Akt and MAPK pathways, all of which are strongly associated with cancer occurrence and progression. TFAP2 is extremely important in the biology of tumours, and knowledge about how and what it does could pave the way for novel therapeutics. Currently, we are investigating treatment with antibodies to TFAP2, and it could well be a promising area for cancer treatment in the future.
References
- MA, MH.; et al. Advances in role of TFAP2α in carcinoma. ACADEMIC JOURNAL OF CHINESE PLA MEDICAL SCHOOL 2016, 37(8): 893-896.
- Nordentoft, I.; et al. Increased expression of transcription factor TFAP2α correlates with chemosensitivity in advanced bladder cancer. BMC cancer 2011, 11: 1-11.
- MA, MH.; et al. Construction of TFAP2α plasmid and its influence on cell proliferation of clear cell renal cancer. ACADEMIC JOURNAL OF CHINESE PLA MEDICAL SCHOOL 2016, 37(7): 773-778.
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