Disease relevance of Smad3

• Nuclear localization of Smad2/Smad3 indicated that the TGF-beta signaling pathway was activated in regressing carcinomas [1].
• In this study, we investigated the expression of Smad2 and Smad3 in an in vivo animal model of lung fibrosis induced by bleomycin [2].
• We found that the expression of Smad3 was regulated in lungs during bleomycin-induced pulmonary fibrosis [2].
• To characterize the function of the TGF-beta signaling intermediates Smad2 and Smad3 in HSC, we infected primary rat HSC in culture with adenoviruses expressing wild-type and dominant negative Smads 2 and 3 [3].
• It thus appears deltaEF1 mediates SMC differentiation via interaction with SRF and Smad3 during development and in vascular disease [4].

High impact information on Smad3

• We report here the cloning and functional studies of a novel mammalian Mad molecule, Mad3, as well as a rat Mad1 homologue [5].
• These results suggest that TGF-beta 1 induces apoptosis through the cleavage of BAD in a Smad3-dependent mechanism [6].
• Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells [6].
• Subpopulations of Smad2/Smad3-positive and apoptotic nuclei colocalized, indicating a role for Smads in apoptosis [1].
• The levels of Smad3 and, in particular, Smad4 were enhanced in the normal ventral prostate, as well as in the tumors after castration [7].

Chemical compound and disease context of Smad3

• Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor [8].
• Naringenin showed a significantly protective effect on experimental rat liver fibrosis, in our efforts to elucidate its antifibrosis molecular mechanisms and to find a novel target based on Smad3 signaling for challenging fibrosis diseases [9].

Biological context of Smad3

• Our results thus demonstrate a novel mechanism of Smad3 function in regulating thyroid cell differentiation by functionally antagonizing the action of the paired domain transcription factor Pax8 [10].
• In contrast, HGF treatment reduced TGF-beta-dependent activation of p15INK4B promoter, in which Smad3 phosphorylation at the C-terminal region was involved [11].
• Down-regulation of Smad2 protein by small interfering RNA duplexes affects only basal transcription of FSH(beta), whereas decreased expression of Smad3 abrogates activin-mediated stimulation of FSH(beta) transcription [12].
• We propose that Smad3 plays an important role in osteoblastic bone formation and might help to elucidate the transcriptional mechanism of bone formation and possibly lead to the development of bone-forming drugs [13].
• We investigated whether these structural features contribute to differential FSH(beta) transactivation by Smad2 and Smad3 [12].

Anatomical context of Smad3

• Previous work from our laboratory demonstrated that Smad3, and not Smad2, is sufficient for stimulation of the rat FSH(beta) promoter in a pituitary-derived cell line L(beta)T2 [12].
• The TGF-beta/activin-restricted Smads were also expressed in a nearly complementary fashion; Smad2 was strongly expressed in proliferating chondrocytes, whereas Smad3 was strongly observed in maturing chondrocytes [14].
• The binding of Smad3 in renal cortical cell nuclei to the Smad-binding element (SBE) was investigated by the electrophoretic mobility shift assay [15].
• We further investigated whether the expression of Smad3 was regulated by TGF-beta in an in vitro lung fibroblast culture system [2].
• TGF-beta mediates activation of Smad2 primarily in early cultured cells and that of Smad3 primarily in transdifferentiated cells [16].

Associations of Smad3 with chemical compounds

• The functional interaction between the paired domain transcription factor Pax8 and Smad3 is involved in transforming growth factor-beta repression of the sodium/iodide symporter gene [10].
• A type I collagen synthesis inhibitor L-azetidine-2-carboxylic acid, as well as osteocalcin (OCN), significantly antagonized Smad3-stimulated ALP activity and mineralization of MC3T3-E1 cells [13].
• Depletion of cellular polyamines by alpha-difluoromethylornithine (DFMO) increased basal levels of Smad3 and Smad4 proteins, induced their nuclear translocation, and stimulated Smad sequence-specific DNA-binding activity [17].
• The decline of Smad3 mRNA was evident at day three of post-bleomycin instillation and the expression of Smad3 continually decreased during the reparative phase of lung injury (days 8 and 12), whereas the expression of Smad2 showed little change after bleomycin administration [2].
• The protein kinase A antagonist H89 abolished the inhibitory effect of PTX on Smad3/4-dependent CTGF transcription, whereas dibutyryl cAMP and forskolin recapitulated the inhibitory effect [8].

Enzymatic interactions of Smad3

• The different regulation of inhibitory Smad-7 was detected in irradiated and irradiated plus anti-TGFbeta1 treated animals by semiquantitative RT-PCR and the nucleocytoplasmic shuttling of phosphorylated Smad-3 was shown by isolation of nuclear proteins and Western blot analysis [18].

Regulatory relationships of Smad3

• In cultured rat granulosa cells from early antral follicles, treatment with GDF-9 stimulated the CAGA-luciferase reporter activity and induced the phosphorylation of Smad3 [19].
• Cotransfection with a Smad3 expressing plasmid further repressed rTERT transcription and c-myc expression, while cotransfection with the corresponding antisense Smad3 construct had the opposite effect [20].

Other interactions of Smad3

• Smad3 mediates activin-induced transcription of follicle-stimulating hormone beta-subunit gene [12].
• Adenoviral overexpression of Smad3 potently repressed inducible expression of endogenous iNOS and IL-6 [21].
• In this study, the role of Smad3 in the inhibition of telomerase reverse transcriptase (TERT) gene transcription by TGFbeta was investigated [20].
• CONCLUSION: Traditional Chinese medicine, JinSanE, prevents the progression of hepatic damage and fibrosis through the inhibition of TGF-beta1, TRII and Smad3 signal proteins, and increases expression of Smad7 signal protein in vivo [22].
• After overexpression of ALK5, with or without exogenous Smad3, the Cos7 cells gained GDF-9 responsiveness based on the CAGA-luciferase reporter assay [19].

Analytical, diagnostic and therapeutic context of Smad3

• The expressions of TGF-beta1, Smad3 and Smad7 in liver tissues were evaluated by immunohistochemistry [23].
• Western blot analyses indicated constitutive phosphorylation of Smad3 in the cells [24].
• The mRNA transcripts of TGF-beta1, PAI-1, Smad3 and 7 were evaluated by real-time PCR [25].
• The mRNA expression of TGF-beta1 and Smad3 of cultured cells and hypertrophic left ventricles were assessed by RT-PCR [26].
• Chromatin immunoprecipitation analysis also demonstrated DNA binding activity of Smad-3 and Smad-4 proteins to the TIMP-1-specific SBE [27].

References