Disease relevance of TGFB1

• The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD) [1].
• Consecutive patients (n = 660) with breast cancer from the Memorial Sloan-Kettering Cancer Center (New York, NY) and healthy females (n = 880) from New York City were genotyped for the hypomorphic TGFBR1*6A allele and for the TGFB1 T29C variant that results in increased TGF-beta circulating levels [2].
• Expression profiling of the influence of RAS mutants on the TGFB1-induced phenotype of the pancreatic cancer cell line PANC-1 [3].
• We hypothesized that functional genetic variants in TGFB1 and TGFBR2 are associated with gastric cancer risk [4].
• Our data suggest that the TGFB1 C-509T variant that affects expression of TGFbeta1 may play a role in advanced stage prostate cancer [5].

Psychiatry related information on TGFB1

• Substantial laboratory evidence suggests Transforming Growth Factor-beta1 (TGFB1) is linked to Alzheimer's Disease (AD) pathology [6].
• To determine the potential role of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and transforming growth factor-beta (TGF-beta) in anorexia nervosa, serum concentrations of these cytokines were measured in patients with anorexia nervosa during starvation and after weight gain [7].
• Therefore, it is essential to delineate the profibrogenic actions of TGF-beta and the influence of alcohol abuse in molecular detail [8].
• Thus transient up-regulation of the components of the TGF-beta receptor complex, and particulartly of endoglin, is associated with heart septation and valve formation during early human development [9].
• Comparatively, there was more variation in TGF-beta1 than TGF-beta3 expression without age or gender relation [10].

High impact information on TGFB1

• IL-13 is the key effector cytokine in asthma and stimulates airway fibrosis through the action of matrix metalloproteinases on TGF-beta and promotes epithelial damage, mucus production, and eosinophilia [11].
• These cells recognize antigen as do all T cells, but they secrete the immunoregulatory cytokines IL-10 and TGF beta [12].
• TGF-beta 1 is produced by every leukocyte lineage, including lymphocytes, macrophages, and dendritic cells, and its expression serves in both autocrine and paracrine modes to control the differentiation, proliferation, and state of activation of these immune cells [13].
• Increased production and activation of latent TGF-beta have been linked to immune defects associated with malignancy and autoimmune disorders, to susceptibility to opportunistic infection, and to the fibrotic complications associated with chronic inflammatory conditions [13].
• IL-10 induces naive B cells to produce IgG3, IgG1, and IgA1, and further addition of TGF beta permits the secretion of IgA2 [14].

Chemical compound and disease context of TGFB1

• In progressive fibrosis of other organs, particularly heart and kidney, production of the profibrogenic cytokine, transforming growth factor beta1 (TGF-beta1), may be enhanced by angiotensin II, the principal effector molecule of the renin-angiotensin system [15].
• The androgen-sensitive and TGF-beta-responsive human prostate cancer cells, LNCaP TbetaRII, were used as in vitro model [16].
• In this study, we have used a tetracycline regulatable RII cDNA expression vector to demonstrate that RII replacement reconstitutes autocrine negative TGF-beta activity in ER(+) breast cancer cells as evidenced by the delayed entry into S phase by the RII transfectants [17].
• Culture supernatants of two human carcinoma cell lines and another murine fibrosarcoma suppressed Mphi NO and TNF-alpha production, which was partly mediated by TGF-beta 1 and prostaglandin E2 [18].
• Characterization of transforming growth factor-beta (TGF-beta) receptors on BeWo choriocarcinoma cells including the identification of a novel 38-kDa TGF-beta binding glycoprotein [19].

Biological context of TGFB1

• In these families, a SNP in the promoter region of TGFB1 (rs2241712) and two SNPs in the 3' genomic region of TGFB1 (rs2241718 and rs6957) were significantly associated with pre- and post-BD FEV(1) (P<0.05) [1].
• Thirty percent of cases were identified as high or low TGF-beta signalers based on TGFB1 and TGFBR1 genotypes [2].
• CED is caused by various missense mutations in the TGFB1 gene that encodes TGFbeta1, the most common of which is an arginine-cysteine amino acid change at codon 218 (R218C) in the latency-associated peptide domain of TGFbeta1 [20].
• The TGF-beta1 (TGFB1) -509T allele was associated with respiratory syncytial virus-related wheezing in the first year (P = .0005) [21].
• The tumor cell lines displayed a gradually inversed gene expression pattern, which correlated with reduced sensitivity to TGFB1, as compared to the HaCaT cell line [22].

Anatomical context of TGFB1

• The frequency of CD25 + memory CD4 + T cells and transient FOXP3 mRNA expression by CD4 + T cells significantly increased after systemic glucocorticoid treatment, whereas TGFB1 expression did not change [23].
• In contrast, two pancreatic carcinoma cell lines, previously found to be growth stimulated by TGFB1, displayed an expression pattern opposite to that of these genes [22].
• In this study, we have investigated whether cultures of cells from normal TA and PD plaques undergo osteogenesis, express markers for stem cells, and originate other cell lineages via processes modulated by TGFB1 [24].
• EGF or TGFB1 alone stimulates but together attenuate granulosa cell DNA synthesis [25].
• Overexpression of TGFB1 was found in the conditioned medium and cellular fractions of both hypertrophic keratinocytes and fibrotic fibroblasts [26].

Associations of TGFB1 with chemical compounds

• TGFB1 expression was not affected by hyperhomocysteinaemia either in normal or in high glucose [27].
• This study was designed for the histopathological, cellular and biochemical characterization of a skin lesion removed surgically from a young male several months after accidental exposure to cesium-137, with an emphasis on expression of transforming growth factor beta1 (TGFB1) and tumor necrosis factor alpha (TNFA) and the occurrence of apoptosis [26].
• This result implicates serine/threonine phosphorylation as an important mechanism of TGF-beta receptor-mediated signaling [28].
• This phenomenon of monocyte deactivation in septic patients with fatal outcome shows similarities to experimental monocytic refractoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-beta (TGF-beta) [29].
• The latter appeared to be involved in the inhibition of proinflammatory cytokine production because addition of exogenous TGF-beta1, prostaglandin E2, or PAF resulted in inhibition of lipopolysaccharide-stimulated cytokine production [30].

Physical interactions of TGFB1

• Excess TGF-beta 1 competes for binding of radioiodinated TGF-beta 1 in a dose-dependent manner and is more effective than TGF-beta 2 [28].
• Smad7 constitutively formed a complex with the TGF-beta receptors, and the inhibitory effect of Smad7 on the promoter activity of human alpha2(I) collagen and 3TP-lux was completely impaired in scleroderma fibroblasts [31].
• Immunoblotting of the fusion protein complexes indicated that the third 8-Cys repeat of LTBP-1 bound covalently to the LAP region of TGF-beta1 [32].
• In both wild-type and mutant cells stably transfected with TGF-beta RII cDNA, TGF-beta RII coimmunoprecipitated with TGF-beta receptor type I in the presence of ligand [33].
• In Ski-transformed cells, all of the Ski protein was found in Smad3-containing complexes that accumulated in the nucleus in the absence of added TGF-beta [34].

Enzymatic interactions of TGFB1

• Members of the SMAD family of intracellular proteins are phosphorylated by TGF-beta receptors and convey signals to specific TGF-beta-inducible genes [35].
• Both Smad2 and Smad3 were phosphorylated in response to TGF-beta1 beginning at 5 minutes, with maximal phosphorylation at 15 minutes, and decreasing phosphorylation by 2 hours [36].
• Smad2 was phosphorylated upon TGF-beta1 treatment, both in the absence and presence of genistein [37].
• Overall, our study indicates that the flux of glucose metabolism through the GFAT catalyzed hexosamine biosynthetic pathway is involved in the glucose-induced mesangial production of TGF-beta leading to increased matrix production [38].
• Both wild-type TGF-beta RI and a kinase-deficient mutant thereof are transphosphorylated by the coexpressed TGF-beta RII kinase in a ligand-independent fashion in these cells [39].

Co-localisations of TGFB1

• CILP colocalized with TGF-beta1 in clustering chondrocytes and their territorial matrices in intervertebral discs [40].

Regulatory relationships of TGFB1

• Thus, SnoN maintains the repressed state of TGF-beta-responsive genes in the absence of ligand and participates in negative feedback regulation of TGF-beta signaling [41].
• Using an in vitro assay, 84-100% of the TGF-beta activity could be blocked with specific antibodies against TGF-beta 2, whereas only 10-21% could be blocked by specific antibodies against TGF-beta 1 [42].
• Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis [43].
• TGF-beta is a ubiquitously expressed cytokine that signals through the Smad proteins to regulate many diverse cellular processes [44].
• We investigated the effects of TGF-beta 1 on the expression of tumoricidal activity induced by IL-2 or interferon-gamma (IFN-gamma) in human monocytes [45].

Other interactions of TGFB1

• Smad2 and Smad4 are related tumour-suppressor proteins, which, when stimulated by the growth factor TGF-beta, form a complex to inhibit growth [46].
• Smad proteins mediate transforming growth factor-beta (TGF-beta) signaling to regulate cell growth and differentiation [41].
• Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein [41].
• Smad3 transactivation and TGF-beta-induced transcription were inhibited by expressing E1A, which interferes with CBP functions [47].
• TNF-alpha, moreover, induced a high degree of resistance to the inhibitory effects of TGF-beta in a dose-dependent way [48].

Analytical, diagnostic and therapeutic context of TGFB1

• METHODS: Using amplification refractory mutation screening PCR, we examined TGFB1 and IL10 gene polymorphisms, which are known to affect cytokine production, in 68 children with moderately severe AD and in 50 nonatopic children [49].
• Transforming growth factor beta-1 (TGFB1)-induced gene expression was studied in five pancreatic carcinoma cell lines and one known TGFB1-sensitive cell line (HaCaT) by use of high-density filter-based cDNA microarrays representing over 4,000 human genes [22].
• To test this hypothesis, we genotyped C-509T and Leu10Pro polymorphisms in TGFB1 and G-875A variant in TGFBR2, using the primer-introduced restriction analysis (PIRA)-PCR assay, in a case-control study of 675 gastric cancer cases and 704 healthy controls in a Chinese population [4].
• Mutations in human BIGH3 (TGFB1), a gene identified after treatment of an adenocarcinoma cell line with TGF-beta, have been observed in patients with granular Groenouw type I, Reis-Bücklers, Thiel-Behnke, Avellino, and Lattice type I and IIIa, six autosomal dominant corneal dystrophies linked to chromosome 5q [50].
• TGFB1 polymorphisms are associated with risk of late normal tissue complications in the breast after radiotherapy for early breast cancer [51].

References