Disease relevance of TGFBR1

• An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder [1].
• CONCLUSIONS: Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease [2].
• RESULTS: We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys-Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz syndrome type II) [2].
• The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively) [2].
• Human umbilical vein endothelial cells (HUVEC) were infected with recombinant adenoviruses carrying a constitutively active form of ALK-1 or ALK-5 [3].

Psychiatry related information on TGFBR1

• FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited [4].
• In endothelial cells, TGF-beta binds to two distinct type I receptor serine-threonine kinases, ALK-5 and ALK-1; the latter activates the same R-Smads that are activated by BMP and induces synthesis of Id (inhibitor of differentiation or inhibitor of DNA binding) proteins [5].

High impact information on TGFBR1

• A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2 [6].
• Thirty percent of cases were identified as high or low TGF-beta signalers based on TGFB1 and TGFBR1 genotypes [7].
• Homozygous deletions of ALK-5 were identified in 1 of 97 pancreatic and 1 of 12 biliary adenocarcinomas [8].
• A germ-line variant of ALK-5, presumably a polymorphism, was identified, but no somatic intragenic mutations were identified upon sequencing of all coding regions of ALK-5 [8].
• However, SPARC silencing in SSc fibroblasts appears not to be associated with TGFBR1- and Smad3-dependent processes [9].

Chemical compound and disease context of TGFBR1

• LNCaP is an androgen-responsive human prostate cancer cell line that has a defective gene for ALK-5, the conventional TGF-beta receptor type I. Yet, these cells respond to exogenous TGF-beta 1 under appropriate concentrations of dihydrotestosterone (DHT) [10].
• Progressive Transforming Growth Factor {beta}1-induced Lung Fibrosis Is Blocked by an Orally Active ALK5 Kinase Inhibitor [11].

Biological context of TGFBR1

• We therefore examined variations in the TGFBR1 gene by PCR, SSCP and RFLP in carcinomas of the urinary system and in tissues from noncancer, age-matched controls [1].
• TGFBR1 activation results in the phosphorylation of intracellular messengers, the SMADs [12].
• ALK-5 inhibited the proliferation, network formation, and tube formation of HUVEC and induced their apoptosis, whereas ALK-1 did not exhibit significant effects on HUVEC in vitro. mRNAs were extracted from HUVEC and used for hybridization of oligonucleotide arrays representing approximately 7,000 human genes [3].
• However, 4 cell lines were methylated within the ALK5 promoter region [13].
• This study assessed a series of bladder tumours and bladder tumour cell lines for sequence variation in the Krüppel-like zinc finger gene ZNF189, the tuberous sclerosis complex gene 1 (TSC1), and the TGF beta receptor type I (TGFBR1) [14].

Anatomical context of TGFBR1

• A G-->A variant 24 bp downstream of the exon/intron 7 boundary of the TGFBR1 gene (Int7G24A) was evident in patients with RCC (46.5%, n = 86) and bladder and upper urinary tract TCC (49.2%, n = 65) significantly more frequently than in age-matched controls (28.3%, n = 113, p < 0.002 by chi2 test) [1].
• To identify target genes of ALK-1 and ALK-5 in endothelial cells, we conducted oligonucleotide microarray analysis [3].
• Here, we deleted the TGF-beta type I receptor gene Alk5 specifically in the embryonic ectodermal and neural crest cell lineages [15].
• ALK5 and SKR1 mRNA levels were 6.8- and 9-fold greater in the pancreatic tumors in comparison with the corresponding levels in the normal pancreas [16].
• To determine whether the inhibition of human osteoblast growth mediated by 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)D3) occurs as a result of changes in transforming growth factor (TGF) and TGF receptor synthesis, we examined the effects of 1 alpha,25(OH)2D3 on the synthesis of TGF beta and TGF-beta receptors [17].

Associations of TGFBR1 with chemical compounds

• One somatic mutation of serine to phenylalanine at codon 57 of the TGFBR1 gene was confirmed in an upper urinary tract TCC [1].
• The length of the polyalanine tract present in exon 1 of the TGFBR1 gene was also investigated [14].
• The p38 mitogen-activated protein kinase inhibitors SB-203580 and SB-202190 also inhibit phosphorylation of Smad3 by ALK5 with IC50 values of 6 and 3 microM, respectively [18].
• A total of eighty-five gene polymorphisms (77 SNPs and 8 indels) were detected in the porcine TGFBR1 gene by utilizing a panel of DNA from eight diversified pig breeds (Yorkshire, Chinese Meishan, Berkshire, Duroc, Hampshire, Landrace, Large White and Pietrain) [19].
• The contractile abilities of normal and dSSc dermal fibroblasts were suppressed by blocking heparin sulfate-containing proteoglycan biosynthesis or antagonizing transforming growth factor-beta receptor type I [activin-linked kinase (ALK5)] or ras/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) [20].

Regulatory relationships of TGFBR1

• The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta [21].
• In contrast, ALK5 inhibition effectively blocked Smad2 phosphorylation [22].
• We have used a gene transfer model of progressive TGF-beta1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of ALK5, the specific TGF-beta receptor [11].
• Both ALK2 and ALK5 are expressed throughout the heart with ALK2 expressed abundantly in endocardial cells of the outflow tract (OFT), ventricle, and AV cushion [23].

Other interactions of TGFBR1

• Assignment of human transforming growth factor-beta type I and type III receptor genes (TGFBR1 and TGFBR3) to 9q33-q34 and 1p32-p33, respectively [24].
• SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7 [25].
• We searched for TGFBR1 and TGFBR2 mutations in 41 unrelated patients fulfilling the diagnostic criteria of Ghent nosology or with the tentative diagnosis of Marfan syndrome, in whom mutations in the FBN1 coding region were not identified [26].
• CONCLUSION: The results indicate that SB431542 is a potent inhibitor of intracellular TGFbeta signaling in normal fibroblasts through selective interference with ALK-5-mediated Smad activation and Smad-dependent transcriptional responses [27].
• In contrast, STAT-6-mediated stimulation of collagen gene expression induced by interleukin-13 was not prevented by SB431542, indicating the specificity of blockade for ALK-5-dependent signaling [27].

Analytical, diagnostic and therapeutic context of TGFBR1

• Another germline deletion (TGFBR1*6A) and somatic mutations in the TGFBR1 were also analyzed by PCR and single-strand conformational polymorphism.RESULTS: The Int7G24A allele was evident in 32% of patients with preinvasive neoplasms and 48% of patients with invasive breast cancers compared with 26% controls (P = 0.00008) [28].
• Int7G24A variant of the TGFBR1 gene and cancer risk: a meta-analysis of three case-control studies [29].
• RT-PCR analysis of LbetaT2 cells and whole adult murine pituitaries indicated that both expressed Tgfbr1 mRNA, but that Tgfbr2 was not detected in LbetaT2 cells [30].
• Increased expression of T beta R-II and ALK-5 proteins in the developing kidney was confirmed by immunohistochemistry [31].
• In contrast, ALK-5 was not detected in these cells by either Western blot analysis or RT-PCR at all concentrations of DHT used in this study [10].

References