Disease relevance of TFAP2A

• Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer [1].
• In this study, we have made a replication-deficient recombinant adenovirus that expresses functional AP-2alpha (Ad-AP2) [2].
• Together, these results support a model in which HIV-1 Nef downregulates CD4 by promoting its accelerated endocytosis by a clathrin/AP2 pathway [3].
• The purpose of our study was to determine AP-2alpha expression distribution among grades of gliomas and any possible effect on prognosis [4].
• Adjacent to this region in HHV-6 are approximately 30 copies of a 103- to 108-bp sequence element, which contains consensus binding sites for the transcription factors AP2 and NF kappa B, in addition to a single KpnI recognition site [5].

Psychiatry related information on TFAP2A

• Sp1 and AP2 transcription factors are required for the human fragile mental retardation promoter activity in SK-N-SH neuronal cells [6].
• Clathrin assembly protein AP-2 is detected in both neurons and glia, and its reduction is prominent in layer II of frontal cortex in Alzheimer's disease [7].

High impact information on TFAP2A

• Binding of clathrin AP-2 (adaptor complex) to an unidentified high affinity membrane receptor appears to be necessary for coated pit assembly in fibroblasts [8].
• We now show that synaptic vesicles have a high affinity AP-2 site (KD, approximately 1 x 10(-10) M) similar to the one observed in fibroblasts [8].
• Multiple synthetic copies of the hMT-IIA high-affinity AP-2 binding site can act as efficient, cell-type-specific enhancer elements; their activity increases after treatment of cells with phorbol ester or cAMP-elevating agents [9].
• AP-2 appears to mediate transcriptional activation in response to two different signal-transduction pathways, one involving the phorbol-ester- and diacylglycerol-activated protein kinase C, the other involving cAMP-dependent protein kinase A [9].
• Juxtaposed binding sites for AP-2 and Sp1 in the 21 bp repeats may facilitate productive interactions between the two factors [10].

Chemical compound and disease context of TFAP2A

• We further show that 5-aza-2'-deoxycytidine induced reexpression of AP-2alpha in MDA-MB-231 breast cancer cells (wherein AP-2alpha expression is silenced by hypermethylation), resulted in massive apoptosis induction, increased chemosensitivity, decreased colony formation, and loss of tumorigenesis upon chemotherapy [11].
• CONCLUSIONS: Our data demonstrate that AP-2alpha expression is associated with normal luminal differentiation and that a loss of AP-2alpha expression occurs early in the development of prostate adenocarcinoma [12].
• Thus, the laboratory night (and presumably the 2 nights at home) preceding AP2 had dramatic increases in apnea compared with the nights preceding C2 [13].
• AIM: To investigate the in vivo anti-tumor effects of total polysaccharide (AP-0) isolated from Angelica sinensis (Oliv.) Diels (Danggui) on mice and the in vitro inhibitory effects of AP-0 and the sub-constituents (AP-1, AP-2 and AP-3) separated from AP-0 on invasion and metastasis of human hepatocellular carcinoma [14].
• After searching for molecules interacting with the leucine-based sorting signals within the cytosolic tail of the major histocompatibility complex class II-associated invariant chain using a phage display approach, we identified phage clones with homology to a conserved region of the AP-1 and AP-2 mu chains [15].

Biological context of TFAP2A

• N-terminal residues of TFAP2A, containing the transactivation domain, are both necessary and sufficient for interaction with p300, and this interaction was independent of CITED2 [16].
• CITED2 interacted with the dimerization domain of TFAP2C, which is highly conserved in TFAP2A/B [16].
• AP-2alpha selectively regulates fragile X mental retardation-1 gene transcription during embryonic development [17].
• Notably, AP-2alpha exhibits a strong gene dosage effect, with heterozygous mice showing approximately 2-fold reduction in Fmr1 levels [17].
• Data obtained with these reagents demonstrate that whereas AP-2alpha and AP-2gamma are both present in benign breast epithelia, there is a significant up-regulation of AP-2gamma expression in breast cancer specimens (P = 0.01) [18].

Anatomical context of TFAP2A

• In addition, prior expression of AP-2alpha increased the chemosensitivity of H460, a lung carcinoma cell line, to adriamycin (2.5-fold) and cisplatin (5-fold) [2].
• Experiments in c-Src depleted cells reveal that AT1R remained mostly colocalized with AP-2 at the plasma membrane after Ang II stimulation, consistent with the observed delay in receptor internalization [19].
• We show that the agonist stimulation of native AT1R in vascular smooth muscle cells (VSMCs) induces the formation of an endogenous complex containing c-Src, beta-arrestins and AP-2 [19].
• Essential role of an activator protein-2 (AP-2)/specificity protein 1 (Sp1) cluster in the UVB-mediated induction of the human vascular endothelial growth factor in HaCaT keratinocytes [20].
• Treatment of MCF-10A and NIH 3T3 cells with the proteasome inhibitor MG-132 showed that AP-2alpha was ubiquitinated and its level significantly increased [21].

Associations of TFAP2A with chemical compounds

• The AP2 transcription factor family is a set of developmentally regulated, retinoic acid inducible genes composed of four related factors, AP2alpha, AP2beta, AP2gamma, and AP2delta [22].
• The phosphotyrosine binding domain of ARH plus either the clathrin box or the AP-2 binding region were required for both clustering and internalization of the LDLR [23].
• Expression of AP-2 in mammalian cells demonstrates that transcriptional activation requires an additional amino-terminal domain that contains an unusually high concentration of proline residues [24].
• Both transient and stable transfection experiments show that AP-2B inhibits AP-2 transactivator function, as measured by an AP-2-responsive chloramphenicol acetyltransferase reporter plasmid [25].
• By monitoring protein-DNA interactions in living cells using formaldehyde cross-linking and chromatin immunoprecipitation, we show that endogenous RB and AP-2 both bind to the same bcl-2 promoter sequence [26].

Physical interactions of TFAP2A

• A highly conserved 20-amino acid sequence in the C-terminal region of ARH bound the beta(2)-adaptin subunit of AP-2 [27].
• In mammalian two-hybrid experiments, full-length p300 and TFAP2A interacted only when CITED2 was co-transfected [16].
• Candidate p53-binding sites were identified in the AP-2alpha and AP-2gamma promoters. p53 binding to these cis-elements in vivo was also observed, together with a relaxation of chromatin structure in these regions [28].
• In vitro studies using coimmunoprecipitation experiments and a yeast three-hybrid assay reveal that c-Src stabilizes the agonist-independent association between beta-arrestin2 and the beta-subunit of AP-2 independently of the kinase activity of c-Src [19].
• We examined the contribution of the new AP-2 binding site to ERBB2 overexpression [29].

Regulatory relationships of TFAP2A

• Furthermore, we demonstrated that AP-2alpha directly interacted with Sp1 to form transcription complexes at two tandem Sp1-binding sites of the promoter to activate KiSS-1 transcription [30].
• The human reduced folate carrier gene is regulated by the AP2 and sp1 transcription factor families and a functional 61-base pair polymorphism [31].
• Thus, the consequence of c-Src in regulating the dissociation of AP-2 from the receptor was also examined on the internalization of AT1R by depleting c-Src in human embryonic kidney (HEK) 293 cells using a small interfering RNA strategy [19].
• Inefficient proteasomal-degradation pathway stabilizes AP-2alpha and activates HER-2/neu gene in breast cancer [21].
• These results demonstrate that AP2 can activate EGF receptor gene expression and may mediate the PMA response of this gene [32].

Other interactions of TFAP2A

• VEGF expression is controlled by the transcription factors activator protein (AP)-1, AP-2, SP-1, and hypoxia-inducible factor 1 [33].
• Our findings support this hypothesis and suggest that in affected individuals, hyperactivation of the AP-2 gene through the overexpression of IR may play a key role in breast carcinogenesis [1].
• Overexpression of AP-2alpha into highly metastatic breast cell lines did not alter KiSS-1 promoter-driven luciferase gene activity [30].
• ARH is a modular adaptor protein that interacts with the LDL receptor, clathrin, and AP-2 [27].
• Strikingly, approximately 80% of the cell lines displayed a simultaneously decreased binding to three or more of these hRFC promoter elements, whereas normal AP-2 binding was retained [34].

Analytical, diagnostic and therapeutic context of TFAP2A

• Chromatin immunoprecipitation showed that AP-2alpha associates with the Fmr1 promoter in vivo [17].
• These results suggest that AP-2alpha inhibits the growth of cells by inducing cell cycle arrest and apoptosis and that the use of AP-2alpha should be explored as a therapeutic strategy either alone or in combination with chemotherapy [2].
• Functional dissection of an AP-2 beta2 appendage-binding sequence within the autosomal recessive hypercholesterolemia protein [35].
• The microarray included normal brain tissue, and AP-2alpha expression was determined by immunohistochemistry [4].
• For this purpose we abolished the new and/or the previously described AP-2 binding sequence by site-directed mutagenesis [29].

References