Disease relevance of SMAD3

• Isoprenoid-mediated control of SMAD3 expression in a cultured model of cystic fibrosis epithelial cells [1].
• One tumor with homozygous loss of SMAD4 was detected, and mutations of this gene were found in four of the 12 carcinomas; no SMAD2 or SMAD3 inactivating genomic alterations were found [2].
• SMAD3 is a transcription factor that mediates TGF-beta1 signaling and is known to be important in many of the cellular processes that regulate fibrosis and inflammation [3].
• Immunohistochemical evaluation of phosphorylated SMAD2/SMAD3 and the co-activator P300 in human glomerulonephritis: correlation with renal injury [4].
• Autocrine regulation of TGF-beta2 production in hypoxia may involve cross-talk between Smad3 and HIF-1alpha signaling pathways, and could be an important mechanism by which endothelial cells respond to hypoxic stress [5].

Psychiatry related information on SMAD3

• Smad3-mediated TGFbeta activity promotes cell-cycle exit and neurogenesis by inhibiting the expression of Id proteins, and activating the expression of neurogenic factors and the cyclin-dependent-kinase-inhibitor p27(kip1) [6].

High impact information on SMAD3

• (2006) answer one of the long-standing questions in the TGFbeta field by identifying a phosphatase, PPM1A, that directly dephosphorylates Smad2 and Smad3 to limit their activation [7].
• Smad3 is a direct mediator of transcriptional activation by the TGFbeta receptor [8].
• We defined how, in the same context, Smad3 can also mediate transcriptional repression of the growth-promoting gene c-myc [8].
• The crystal structure of a Smad3 MH1 domain bound to an optimal DNA sequence determined at 2.8 A resolution reveals a novel DNA-binding motif [9].
• These interactions complement interactions between c-Jun and c-Fos, and between Smad3 and Smad4 [10].

Chemical compound and disease context of SMAD3

• From transforming growth factor-beta signaling to androgen action: identification of Smad3 as an androgen receptor coregulator in prostate cancer cells [11].
• Smad3 mediates angiotensin II- and TGF-beta1-induced vascular fibrosis: Smad3 thickens the plot [12].
• Surprisingly, although Smad3 null mice, deficient in TGF-beta signal transmission, are resistant to bleomycin- and TGF-beta-mediated fibrosis, they develop spontaneous age-related airspace enlargement, consistent with emphysema, with a lack of ability to repair tissue damage appropriately [13].

Biological context of SMAD3

• SMAD3/4-dependent transcriptional activation of the human type VII collagen gene (COL7A1) promoter by transforming growth factor beta [14].
• Inhibition of the transforming growth factor beta (TGFbeta) pathway by interleukin-1beta is mediated through TGFbeta-activated kinase 1 phosphorylation of SMAD3 [15].
• Cotransfection of SMAD3-SMAD4 along with hepatocyte nuclear factor-4 resulted in a strong synergistic transactivation of the -890/+24 apoCIII promoter, proximal promoter segments, or synthetic promoters containing either the apoCIII enhancer or the proximal apoCIII hormone response element [16].
• IL-1beta and its downstream mediator TAK1 inhibit SMAD3-mediated TGFbeta target gene activation, whereas SMAD3 nuclear translocation and DNA binding in response to TGFbeta are not affected [15].
• Radioresistance was abrogated by reinsertion of the human SMAD3 transgene, resulting in a D(0)=1.49 0.10 (P=0.028) for Smad3(-/-)(3) cells [17].

Anatomical context of SMAD3

• Electrophoretic mobility-shift assays with nuclear extracts from COS-1 cells transfected with expression vectors for SMADs 1-5 indicate that SMAD3 forms a complex with a migration similar to that of the endogenous TGF-beta-specific complex observed in fibroblast extracts [14].
• The goal of this study was to identify a mechanism leading to reduced SMAD3 protein expression in CF epithelium [1].
• SMAD3 expression is regulated by mitogen-activated protein kinase kinase-1 in epithelial and smooth muscle cells [3].
• TGF-beta-dependent differentiation of these cells to monocytes, but not retinoic acid-dependent differentiation to granulocytes, was accompanied by rapid phosphorylation and nuclear translocation of Smad2 and Smad3 [18].
• Overexpressed Smad3 strongly induced the primary chondrogenesis of human mesenchymal stem cells [19].

Associations of SMAD3 with chemical compounds

• Orphan Nuclear Receptor Small Heterodimer Partner Inhibits Transforming Growth Factor-beta Signaling by Repressing SMAD3 Transactivation [20].
• Cyclic adenosine 3',5'-monophosphate-elevating agents inhibit transforming growth factor-beta-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism [21].
• TGF-beta signals through its cell surface receptor serine kinases that phosphorylate Smad2 or Smad3 proteins [22].
• Using transient transfection systems, we demonstrated that Smad3 specifically represses transcriptional activation mediated by AR on two natural androgen-responsive promoters [23].
• The induction of MMP-13 expression by Smad3 and constitutively active mutants of MKK3b or MKK6b was blocked by specific p38 inhibitor SB203580 and by the dominant negative form of p38alpha [24].

Physical interactions of SMAD3

• In addition, TGFbeta induces the binding of a Smad3/Smad4-containing nuclear complex to CAGA boxes [25].
• In conclusion, our data demonstrate for the first time that ligand-bound AR inhibits TGF-beta transcriptional responses through selectively repressing the binding of Smad3 to SBE [26].
• UV irradiation reduced protein binding to the Smad3 enhancer and increased binding to the AP-1 enhancer [27].
• Finally, we show that GR interacts with Smad3 both in vitro and in vivo [28].
• Here, we show that c-Ski and SnoN bind to the "SE" sequence in the C-terminal MH2 domain of Smad3, which is exposed on the N-terminal upper side of the toroidal structure of the MH2 oligomer [29].

Enzymatic interactions of SMAD3

• 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 [30].
• Smad2 and Smad3 were phosphorylated in response to activin and accumulated in the nucleus of treated T47D cells [31].
• We investigated the mechanism of phosphorylation-induced Smad complex formation with an activating pseudo-phosphorylated Smad3 [32].

Co-localisations of SMAD3

• In the absence of ligand stimulation, Axin was colocalized with Smad3 in the cytoplasm in vivo [33].

Regulatory relationships of SMAD3

• Dominant-negative Smad3 inhibited the transcriptional synergistic response by Smad2 and Smad4 [34].
• A dominant negative mutant form of Smad3 lacking the C-terminal serine phosphoacceptor sites (Smad3A) inhibited TGF-beta1-induced luciferase activity [30].
• Using mammalian two-hybrid assays, we demonstrate that GR inhibits transcriptional activation by both Smad3 and Smad4 C-terminal activation domains [28].
• SMAD3 represses androgen receptor-mediated transcription [23].
• Addition of Ets1 greatly enhanced the Smad3/TGF beta-mediated activation [35].

Other interactions of SMAD3

• Smad2 and Smad3 are structurally highly similar and mediate TGF-beta signals [34].
• In addition, we observed TbetaR-activation-dependent interaction between Smad2 and Smad3 [34].
• Evi-1 interacted with and repressed the receptor-activated transcription through Smad1 and Smad2, similarly to Smad3 [36].
• RESULTS: Protein and mRNA levels of SMAD3, but not of SMAD4 or SMAD7, were variably elevated in scleroderma fibroblasts compared with those from healthy controls [37].
• Modifying the interaction between Smad3 and TERT gene may, thus, lead to novel strategies to regulate telomerase [38].
• Reduction in the expression or activity of Axin/GSK3-beta leads to increased Smad3 stability and transcriptional activity without affecting TGF-beta receptors or Smad2, whereas overexpression of these proteins promotes Smad3 basal degradation and desensitizes cells to TGF-beta [39].

Analytical, diagnostic and therapeutic context of SMAD3

• Co-immunoprecipitation and GST pull-down assays provided evidence for physical interactions between SMAD3, SMAD4, and hepatic nuclear factor-4 [16].
• Using a mammalian two hybrid assay, we found physical and functional interactions between SMAD3 and both NKX2.1 and HNF-3 [40].
• Further studies confirm that promoter activity correlates with protein expression by demonstrating reduced SMAD3 protein expression in A549 cells and airway smooth muscle cells after treatment with MEK1 inhibitors [3].
• Inactive, GDP-locked RanT24N or nuclear microinjection of Ran GTPase activating protein 1 blocked Smad3 export [41].
• Chromatin immunoprecipitation experiments confirmed interaction of Smad3 with JunB and Cbfa1/Runx2 [42].

References