Disease relevance of TGFA

• The first association study of cleft lip with or without cleft palate (CL/P), with candidate genes, found an association with the transforming growth-factor alpha (TGFA) locus [1].
• Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate [2].
• The role of epidermal growth factor receptor (EGF-R) and transforming growth factor alpha (TGFA) in endometrial cancer is still controversial [3].
• EGF-R and TGFA coexpression appeared as a constant feature of benign squamous metaplasia [3].
• Conversely, in mucinous and serous papillary adenocarcinoma, EGF-R and TGFA immunostaining was not observed [3].

Psychiatry related information on TGFA

• Here we assess possible interaction between the child's TGFA TaqI A2A2 genotype and maternal cigarette smoking, alcohol consumption, use of multivitamins and folic acid [4].
• The existence of an autocrine loop for self-stimulation of growth in malignant cells has been proposed for transforming growth factor-alpha (TGF alpha) and its receptor, the epidermal growth factor (EGF) receptor, in a variety of malignant cell types [5].
• These findings provide evidence that TGF-alpha up-regulates TLR expression and function, augmenting host defense mechanisms at epithelial surfaces [6].

High impact information on TGFA

• Cells that contain high affinity EGF-R are at approximately the BFU-E stage, and their long-term renewal can be induced by TGF alpha [7].
• TGF beta 1 may have an important role in the pathogenesis of fibrosis in patients with chronic liver disease, and TGF alpha expression may be associated with liver regeneration in these patients [8].
• TGF alpha is a hepatocyte mitogen that participates in liver regeneration [8].
• The 50 amino acid form of TGF-alpha is cleaved from a conserved integral membrane glycoprotein by a protease that, in many tumor cells, appears to be limiting [9].
• However, membrane-bound TGF-alpha forms remain on the surface of TGF-alpha-expressing cell lines [10].

Chemical compound and disease context of TGFA

• In conclusion, we find little evidence of interaction between the child's genotypes at TGFA TaqI and various exposures for cleft palate, with the possible exception of folic acid intake [4].
• Clones of the EGFR expressing glioma cell line U-1242 MG were transfected with TGF-alpha cDNA using a tetracycline-inhibitory system for gene expression [11].
• Retinoic acid normalizes the increased gene transcription rate of TGF-alpha and EGFR in head and neck cancer cell lines [12].
• Transforming growth factor alpha (TGF alpha)-Pseudomonas exotoxin 40 (PE40) is a chimeric protein consisting of an N-terminal TGF alpha domain fused to a C-terminal 40-kDa segment of the Pseudomonas exotoxin A protein [13].
• In neuroblastoma cells, 17 beta-estradiol treatment induced a transient increase in the transcription of estrogen-responsive element-containing promoters including those regulating TGF-alpha and prothymosin alpha synthesis [14].

Biological context of TGFA

• Significant associations with the TGFA TaqI and BamHI RFLPs were confirmed, although associations of clefting with previously reported haplotypes did not reach significance [1].
• Here we extend our original analysis of the TGFA TaqI RFLP to two other TGFA RFLPs and seven other RFLPs at five candidate genes in 117 nonsyndromic cases of CL/P and 113 controls [1].
• An allelic association between the transforming growth factor alpha gene (TGFA) situated in the chromosome 2p13 region and nonsyndromic cleft lip with or without cleft palate, also named orofacial cleft (OFC), was found in several population studies [15].
• The gene for hexokinase II, HK2, has been previously mapped to human chromosome 2p13 by fluorescence in situ hybridization, and two-point linkage analysis has placed it near the locus for transforming growth factor alpha, TGFA [16].
• Collectively, our findings indicate that disruption of the TGFA/EGFR/MAPK pathway may represent a strategy that could be exploited to manipulate prostate carcinoma growth and cell survival after irradiation [17].

Anatomical context of TGFA

• Because EGFR and TGFA expression were routinely found in normal squamous epithelium, overexpression was considered present if greater uptake of the antibody was manifested by a deeper immunostain [18].
• Working with a cloned cDNA probe (lambda hTGF1-10) and derivatives, we have mapped this gene (TGFA) to 2p13 with the use of somatic cell hybrids and in situ hybridization [19].
• Using another monoclonal antibody directed to TGF-alpha, immunohistochemistry showed a different pattern of positive cells including eosinophilic precursor cells, in accordance with earlier findings in blood eosinophils [20].
• The expression of transforming growth factor-alpha (TGF-alpha) in human differentiating leukemic cell lines and in circulating human eosinophils prompted the search for an analogous function in normal human bone marrow (BM) cells [20].
• The presence of membrane-bound TGF-alpha on erythroblasts was confirmed by immunomagnetic cell sorting with polyclonal TGF-alpha antibodies; the recovered cells consisted almost entirely of erythroblasts [20].

Associations of TGFA with chemical compounds

• Two potential CL +/- P susceptibility loci (CSL), transforming growth factor alpha (TGFA) and retinoic acid receptor (RARA), have been identified through association studies [21].
• AREG and TGFA are biomarkers for Gefitinib non-responders [22].
• The risk associated with two copies of the A2 allele at TGFA TaqI was strong among children whose mothers did not use folic acid (relative risk=4.5, 95% confidence interval=1.3-15.7), and was only marginal among children whose mothers reported using folic acid (RR=1.4, 95% CI=0.2-12.7) [4].
• DESIGN: We examined the C2/TaqI variant of the TGFA gene in 536 patients with nonsyndromic CL/P and 412 controls [23].
• Furthermore, the antibody neutralizing the TGF-alpha binding to an EGF receptor was able to reduce the DNA synthesis associated with the vitamin A deficiency [24].

Physical interactions of TGFA

• This reduced binding is not due to an occupation of the receptors by TGF-alpha since the expression level of this mitogen in different KS cell lines does not correlate with their capacity to bind EGF [25].
• Expression of wild-type EGFR ligands, such as transforming growth factor-alpha (TGF-alpha) or heparin-binding EGF (HB-EGF), is also often increased in gliomas resulting in an autocrine loop that contributes to the growth autonomy of glioma cells [26].
• We now demonstrate that transmembrane TGF-alpha physically interacts with CD9, a protein with four membrane spanning domains that is frequently coexpressed with TGF-alpha in carcinomas [27].
• NF-IL-6 binding to a 32P-labeled NF-IL-6 binding sequence was enhanced 20 min after TGF-alpha stimulation and returned to basal levels within 90 min, whereas NFkappaB binding activity was enhanced after 20 min and returned to normal 60 min after stimulation [28].
• Neo transfected cells that did not express ER alpha or cells stably transfected with the DNA binding domain mutant C202R/E203V which prevents gene activation did not induce TGF alpha mRNA after either E(2) or 4-OHT treatment [29].

Enzymatic interactions of TGFA

• Accompanying the increase in KGF there was also an increase in TGF-alpha precursor proteins in the culture supernatants and the phosphorylated form of the EGFR receptor was also detected in the tissue [30].
• Tumor necrosis factor alpha-converting enzyme (TACE) is reported to cleave precursor of TGF-alpha, with release of soluble mature TGF-alpha in various epithelial tissues [31].
• ADAM 10 correctly cleaves peptides and a soluble form of precursor TGF-alpha (proTGFecto) at the N-terminal site but not the C-terminal site [32].

Regulatory relationships of TGFA

• The ability of TCDD to stimulate the EGFR pathway and inhibit apoptosis may be due to the ability of TCDD to increase expression of TGF-alpha, a ligand for EGFR [33].
• IGF-1 also induced production and secretion of TGF-alpha and AR proteins as detected by immunoassays [34].
• However, if the protein is fused with the AR heparin-binding domain, TGF-alpha secretion is inhibited unless the AR pro-region is also present [35].
• The binding of HB-EGF to tumour cells is blocked by mAbs which act as EGF and TGF alpha antagonists [36].
• In contrast, in HOME cells, t-PA activity and tube-like structures were induced in the presence of TGF-alpha alone, but not in the presence of HGF alone [37].

Other interactions of TGFA

• The present analyses were undertaken to determine whether D4S175 or D4S192 is significantly associated with CL +/- P in a sample of unrelated patients that have previously provided evidence of associations between CL +/- P and both TGFA and RARA [21].
• These results suggest that vitamin A plays an important regulatory role in the paracrine/autocrine secretion of EGF/TGF-alpha-like mitogen in TBE cell cultures [24].
• These results suggested the expression of a TGF alpha/EGFR autocrine mechanism in this cell line [38].
• In a multivariate analysis, both TGF-alpha (P < 0.0001) and HER2 (P = 0.045) were independently correlated with ERK1/2 activation [39].
• TGF beta did not enhance the expression of mRNA for aFGF or TGF alpha in keratinocytes [40].

Analytical, diagnostic and therapeutic context of TGFA

• In addition, no evidence was found for an association of TGFA with CL/P in this case-control study [23].
• Immunprecipitation and Western blot analysis showed that BPH tissue contained the corresponding proteins, EGF and TGF alpha [41].
• Both cell lines expressed the same level of EGF receptors, as assessed by flow cytometry; however, MGLVA1 did not have enhanced in vitro proliferation in response to EGF or TGF-alpha, unlike C170HM2 [42].
• We have examined levels of epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) in neoplastic and non-neoplastic bladder tissue using a standard radioimmunoassay technique [43].
• Northern blot analysis revealed that bands corresponding to hTGF-alpha mRNA were present in melanoma cell lines producing a large amount of IR-TGF-alpha, indicating that the TGF-alpha produced is the product of hTGF-alpha gene [44].

References