Genomes and Genes
Summary: An inhibitory smad protein that associates with TRANSFORMING GROWTH FACTOR BETA RECEPTORS and BONE MORPHOGENETIC PROTEIN RECEPTORS. It negatively regulates SIGNAL TRANSDUCTION PATHWAYS by inhibiting PHOSPHORYLATION of RECEPTOR-REGULATED SMAD PROTEINS.
- Yan X, Liu Z, Chen Y. Regulation of TGF-beta signaling by Smad7. Acta Biochim Biophys Sin (Shanghai). 2009;41:263-72 pubmed..Overexpression of Smad7 has been shown to antagonize TGF-beta-mediated fibrosis, carcinogenesis, and inflammation, suggesting a therapeutic potential of Smad7 to treat these diseases. ..
- Boirivant M, Pallone F, Di Giacinto C, Fina D, Monteleone I, Marinaro M, et al. Inhibition of Smad7 with a specific antisense oligonucleotide facilitates TGF-beta1-mediated suppression of colitis. Gastroenterology. 2006;131:1786-98 pubmed..This may represent a new approach to the control of IBD, particularly during active phases when its Smad7 profile resembles that of hapten-induced colitis. ..
- del Pilar Alatorre Carranza M, Miranda Díaz A, Yañez Sánchez I, Pizano Martínez O, Hermosillo Sandoval J, Vazquez Del Mercado M, et al. Liver fibrosis secondary to bile duct injury: correlation of Smad7 with TGF-beta and extracellular matrix proteins. BMC Gastroenterol. 2009;9:81 pubmed publisher..We also observed greater expression of Col I and Col III mRNA in BDI patients and significant correlations between their expression and TGF-beta concentration and Smad7 mRNA expression. ..
- Hong S, Lee C, Kim S. Smad7 sensitizes tumor necrosis factor induced apoptosis through the inhibition of antiapoptotic gene expression by suppressing activation of the nuclear factor-kappaB pathway. Cancer Res. 2007;67:9577-83 pubmed..These findings suggest that Smad7 sensitizes the tumor cells to TNF-induced apoptosis through the inhibition of expression of antiapoptotic NF-kappaB target genes. ..
- Kleiter I, Pedre X, Mueller A, Poeschl P, Couillard Despres S, Spruss T, et al. Inhibition of Smad7, a negative regulator of TGF-beta signaling, suppresses autoimmune encephalomyelitis. J Neuroimmunol. 2007;187:61-73 pubmed..Elevated Smad7 protein expression was found in the spinal cord of SJL/J mice and DA rats with experimental autoimmune ..
- Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal V, et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med. 2010;207:1589-97 pubmed publisher..These experiments demonstrate an important role for miR-21 in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory fibrotic diseases, such as IPF. ..
- Liu Z, Huang X, Lan H. Smad3 mediates ANG II-induced hypertensive kidney disease in mice. Am J Physiol Renal Physiol. 2012;302:F986-97 pubmed publisher..Results from this study suggest that inhibition of Smad3 or overexpression of Smad7 may be a novel therapeutic strategy for hypertensive nephropathy. ..
- Dooley S, Hamzavi J, Ciuclan L, Godoy P, Ilkavets I, Ehnert S, et al. Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage. Gastroenterology. 2008;135:642-59 pubmed publisher..Furthermore, ablation of TGF-beta signaling specifically in this cell type is sufficient to blunt the fibrogenic response. ..
- Hong S, Lim S, Li A, Lee C, Lee Y, Lee E, et al. Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2. Nat Immunol. 2007;8:504-13 pubmed..Thus, Smad7 is a critical mediator of TGF-beta signals that block proinflammatory TNF signals. ..
- Pittman A, Naranjo S, Webb E, Broderick P, Lips E, van Wezel T, et al. The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression. Genome Res. 2009;19:987-93 pubmed publisher..We propose that the novel SNP we have identified is the functional change leading to CRC predisposition through differential SMAD7 expression and, hence, aberrant TGF-beta signaling...
- Gibson L, Johnson N, Fraser A, dos Santos Silva I, Houlston R, Peto J, et al. No breast cancer association for transforming growth factor-beta pathway colorectal cancer single nucleotide polymorphisms. Cancer Epidemiol Biomarkers Prev. 2009;18:1934-6 pubmed publisher..94 or >1.08. One or more of these variants may be associated with a very small OR for breast cancer, but our data suggest that the effects of these alleles are cancer site-specific. ..
- Hneino M, François A, Buard V, Tarlet G, Abderrahmani R, Blirando K, et al. The TGF-?/Smad repressor TG-interacting factor 1 (TGIF1) plays a role in radiation-induced intestinal injury independently of a Smad signaling pathway. PLoS ONE. 2012;7:e35672 pubmed publisher..In conclusion, the TGF-?/Smad co-repressor TGIF1 plays a role in radiation-induced normal tissue damage by a Smad-independent mechanism. ..
- Shukla M, Rose J, Ray R, Lathrop K, Ray A, Ray P. Hepatocyte growth factor inhibits epithelial to myofibroblast transition in lung cells via Smad7. Am J Respir Cell Mol Biol. 2009;40:643-53 pubmed publisher..HGF-dependent decrease in alpha-SMA was abolished with specific siRNAs targeted to Smad7. Thus, induction of Smad7 by HGF serves to limit acquisition of the myofibroblast phenotype in alveolar epithelial cells. ..
- Lan H. Smad7 as a therapeutic agent for chronic kidney diseases. Front Biosci. 2008;13:4984-92 pubmed..These findings also indicate that targeting the TGF-beta/Smad signaling pathway by overexpressing Smad7 may provide a novel, specific, and effective therapy for chronic kidney diseases. ..
- Hamzavi J, Ehnert S, Godoy P, Ciuclan L, Weng H, Mertens P, et al. Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in mice. J Cell Mol Med. 2008;12:2130-44 pubmed publisher..Studies with primary hepatocytes from S7DeltaE1 and wild-type mice indicate that in the absence of functional Smad7 protein, hepatocytes are more sensitive for TGF-beta effects resulting in enhanced cell death...
- Yang F, Huang X, Chung A, Hou C, Lai K, Lan H. Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition. J Pathol. 2010;221:390-401 pubmed publisher..Smad3, but not Smad2, may be a mediator of EMT, while Smad7 may play a protective role in EMT in response to Ang II. ..
- Chung A, Huang X, Zhou L, Heuchel R, Lai K, Lan H. Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice. Nephrol Dial Transplant. 2009;24:1443-54 pubmed publisher..The present study tested the hypothesis that disruption of Smad7 function may accelerate renal fibrosis and inflammation...
- Dominitzki S, Fantini M, Neufert C, Nikolaev A, Galle P, Scheller J, et al. Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25 T cells. J Immunol. 2007;179:2041-5 pubmed
- Jungert K, Buck A, Buchholz M, Wagner M, Adler G, Gress T, et al. Smad-Sp1 complexes mediate TGFbeta-induced early transcription of oncogenic Smad7 in pancreatic cancer cells. Carcinogenesis. 2006;27:2392-401 pubmed..We thus conclude that Sp1 strongly contributes to the aberrant transcriptional response of transformed epithelial cells to TGFbeta stimulation. ..
- Passarelli M, Coghill A, Hutter C, Zheng Y, Makar K, Potter J, et al. Common colorectal cancer risk variants in SMAD7 are associated with survival among prediagnostic nonsteroidal anti-inflammatory drug users: a population-based study of postmenopausal women. Genes Chromosomes Cancer. 2011;50:875-86 pubmed publisher..33-5.37] and each minor allele of rs4464148 was associated with better survival (HR = 0.41, CI 0.18-0.94). SMAD7 variants known to be important for CRC risk were associated with disease-specific survival among prediagnostic NSAID users. ..
- Zhao Y, Thornton A, Kinney M, Ma C, Spinner J, Fuss I, et al. The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor ? (TGF-?) signaling and the development of regulatory T cells. J Biol Chem. 2011;286:40520-30 pubmed publisher..Together, our results show that CYLD regulates TGF-? signaling function in T cells and the development of Tregs through deubiquitination of Smad7. ..
- Broderick P, Sellick G, Fielding S, Catovsky D, Houlston R. Lack of a relationship between the common 18q24 variant rs12953717 and risk of chronic lymphocytic leukemia. Leuk Lymphoma. 2008;49:271-2 pubmed publisher..99 (95% CI: 0.85 - 1.16) and 0.91 (95% CI: 0.74 - 1.11) for heterozygotes and TT homozygotes, respectively. These data suggests variation at SMAD7 does not significantly contribute to an inherited susceptibility to CLL. ..
- Hong S, Kim H, Kim J, Ha H, Kim Y, Bae E, et al. Smad7 protein induces interferon regulatory factor 1-dependent transcriptional activation of caspase 8 to restore tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. J Biol Chem. 2013;288:3560-70 pubmed publisher..In conclusion, we suggest a novel role for Smad7 as a transcriptional coactivator for caspase 8 through the interaction with IRF1 in regulation of the cell death pathway. ..
- Tang Y, Liu Z, Zhao L, Clemens T, Cao X. Smad7 stabilizes beta-catenin binding to E-cadherin complex and promotes cell-cell adhesion. J Biol Chem. 2008;283:23956-63 pubmed publisher..Thereby, rather than being translocated to the nucleus for regulating the target gene transcription, Smad7-stabilized-beta-catenin is shunted to the E-cadherin complex to modulate cell-cell adhesion. ..
- Ka S, Huang X, Lan H, Tsai P, Yang S, Shui H, et al. Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice. J Am Soc Nephrol. 2007;18:1777-88 pubmed..05). This study provides important evidence that overexpression of Smad7 may have therapeutic potential for autoimmune kidney disease. ..
- Fuchshofer R, Stephan D, Russell P, Tamm E. Gene expression profiling of TGFbeta2- and/or BMP7-treated trabecular meshwork cells: Identification of Smad7 as a critical inhibitor of TGF-beta2 signaling. Exp Eye Res. 2009;88:1020-32 pubmed publisher..A therapeutic modulation of Smad7 might be a promising approach to influence ECM turnover in the TM and to treat POAG. ..
- Tojo M, Takebe A, Takahashi S, Tanaka K, Imamura T, Miyazono K, et al. Smad7-deficient mice show growth retardation with reduced viability. J Biochem. 2012;151:621-31 pubmed publisher..We demonstrated that Smad7 plays an important role in normal mouse growth and provide a useful tool for analysing Smad7 functions in vivo. ..
- Ekman M, Mu Y, Lee S, Edlund S, Kozakai T, Thakur N, et al. APC and Smad7 link TGF? type I receptors to the microtubule system to promote cell migration. Mol Biol Cell. 2012;23:2109-21 pubmed publisher..Moreover, the Smad7-APC complex links the TGF? type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGF?. ..
- Thompson C, Plummer S, Acheson L, Tucker T, Casey G, Li L. Association of common genetic variants in SMAD7 and risk of colon cancer. Carcinogenesis. 2009;30:982-6 pubmed publisher..015 for rs4939827 and P = 0.061 for rs12953717). Similar effect modification was found in haplotype analyses. Our data add evidence supporting these genetic variants as markers predisposing to colon cancer, specifically in women. ..
- Slattery M, Herrick J, Curtin K, Samowitz W, Wolff R, Caan B, et al. Increased risk of colon cancer associated with a genetic polymorphism of SMAD7. Cancer Res. 2010;70:1479-85 pubmed publisher..No significant associations were observed for the rs4464148 SNP or other SNPs evaluated in the SMAD7. These results corroborate the findings of GWAS in colon cancer pointing to SMAD7 and reinforce interest in SNPs in this gene. ..
- Song Q, Zhu B, Hu W, Cheng L, Gong H, Xu B, et al. A common SMAD7 variant is associated with risk of colorectal cancer: evidence from a case-control study and a meta-analysis. PLoS ONE. 2012;7:e33318 pubmed publisher..Nevertheless, fine-mapping of the susceptibility loci defined by rs4939287 should be imposed to reveal causal variant. ..
- Gutierrez Aguilar R, Benmezroua Y, Balkau B, Marre M, Helbecque N, Charpentier G, et al. Minor contribution of SMAD7 and KLF10 variants to genetic susceptibility of type 2 diabetes. Diabetes Metab. 2007;33:372-8 pubmed..Although the observed association of SMAD7 and KLF10 gene variants with T2D is modest, they may weakly contribute to a particular genetic background that increases the susceptibility to development of T2D. ..
- Liu F, Li X, Peng Y, Liu H, Liu Y. Arkadia-Smad7-mediated positive regulation of TGF-beta signaling in a rat model of tubulointerstitial fibrosis. Am J Nephrol. 2007;27:176-83 pubmed..levels of Arkadia, Smurf2, TbetaRI, TGF-beta1 mRNA, type 1 collagen mRNA, and Smad7 mRNA, and low levels of Smad7 protein in the kidneys of rats with unilateral ureteral obstruction, in which Smurf2 interacted with both Smad7 and ..
- Javelaud D, Mohammad K, McKenna C, Fournier P, Luciani F, Niewolna M, et al. Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis. Cancer Res. 2007;67:2317-24 pubmed..Blockade of TGF-beta signaling may be an effective treatment for melanoma metastasis to bone. ..
- Zhang S, Ekman M, Thakur N, Bu S, Davoodpour P, Grimsby S, et al. TGFbeta1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner. Cell Cycle. 2006;5:2787-95 pubmed..Our data imply that Smad7 plays a crucial role upstream of ATM and p53 to protect the genome from insults evoked by extracellular stress. ..
- Alejandre Alcazar M, Michiels Corsten M, Vicencio A, Reiss I, Ryu J, de Krijger R, et al. TGF-beta signaling is dynamically regulated during the alveolarization of rodent and human lungs. Dev Dyn. 2008;237:259-69 pubmed..These data suggest that active TGF-beta signaling is required for normal late lung development. ..
- Li X, YANG X, Hu N, Sun J, LI F, Li M. A risk-associated single nucleotide polymorphism of SMAD7 is common to colorectal, gastric, and lung cancers in a Han Chinese population. Mol Biol Rep. 2011;38:5093-7 pubmed publisher..294 (95% CI, 1.537-3.343, P < 1 × 10(-4)), respectively, for colorectal, gastric, lung, and combined cancers. These outcomes suggest that rs12953717 is a common risk marker of these three types of cancer in the Han Chinese. ..
- Tang S, Snider P, Firulli A, Conway S. Trigenic neural crest-restricted Smad7 over-expression results in congenital craniofacial and cardiovascular defects. Dev Biol. 2010;344:233-47 pubmed publisher..Taken together, the data illustrate that tightly regulated TGFbeta superfamily signaling plays an essential role during craniofacial and cardiac NCC colonization and cell survival in vivo. ..
- Geng Z, Zheng J, Zhang X, Tao J, Wang L. Role of transforming growth factor-beta signaling pathway in pathogenesis of benign biliary stricture. World J Gastroenterol. 2008;14:4949-54 pubmed..The high expression of TGF-beta/Smad/CTGF signaling pathway plays an important role in the pathogenesis of benign biliary stricture. ..
- Wang M, Hada M, Huff J, Pluth J, Anderson J, O Neill P, et al. Heavy ions can enhance TGF? mediated epithelial to mesenchymal transition. J Radiat Res. 2012;53:51-7 pubmed
- Monteleone G, Boirivant M, Pallone F, MacDonald T. TGF-beta1 and Smad7 in the regulation of IBD. Mucosal Immunol. 2008;1 Suppl 1:S50-3 pubmed publisher..These data support a role for Smad7 in maintaining intestinal inflammation, and suggest that blocking Smad7 could be a promising way to dampen the ongoing inflammation in IBD. ..
- Broderick P, Carvajal Carmona L, Pittman A, Webb E, Howarth K, Rowan A, et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet. 2007;39:1315-7 pubmed..Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12)). ..
- Zhong R, Zou L, Sheng W, Zhu B, Xiang H, Chen W, et al. Genetic variations in the TGF? signaling pathway, smoking and risk of colorectal cancer in a Chinese population. Carcinogenesis. 2013;34:936-42 pubmed publisher..162×10(-6), 8.574×10(-8) and 9.410×10(-8) in combined analyses, respectively. This study emphasized the substantial role of the TGF? signaling pathway in CRC, especially in interaction with smoking. ..
- Blank U, Karlsson G, Moody J, Utsugisawa T, Magnusson M, Singbrant S, et al. Smad7 promotes self-renewal of hematopoietic stem cells. Blood. 2006;108:4246-54 pubmed..Taken together, these data reveal an important and previously unappreciated role for the Smad-signaling pathway in the regulation of self-renewal of HSCs in vivo. ..
- Fujii T, Ohtsuka Y, Lee T, Kudo T, Shoji H, Sato H, et al. Bifidobacterium breve enhances transforming growth factor beta1 signaling by regulating Smad7 expression in preterm infants. J Pediatr Gastroenterol Nutr. 2006;43:83-8 pubmed..These results demonstrated that the administration of B. breve to preterm infants can up-regulate TGF-beta1 signaling and may possibly be beneficial in attenuating inflammatory and allergic reactions in these infants. ..
- Chang Y, Liu C, Yang J, Liu G, Feng F, Tang J, et al. MiR-20a triggers metastasis of gallbladder carcinoma. J Hepatol. 2013;59:518-27 pubmed publisher..TGF-?1-mediated activation of the miR-20a/Smad7/?-catenin axis plays a pivotal role in the pathogenesis and worse prognosis of GBCs and may serve as a potential therapeutic target in the future. ..
- Han G, Li F, Ten Dijke P, Wang X. Temporal smad7 transgene induction in mouse epidermis accelerates skin wound healing. Am J Pathol. 2011;179:1768-79 pubmed publisher..In sum, epidermal Smad7 overexpression accelerated wound healing through its direct effects on keratinocyte proliferation and migration, and through indirect effects on wound stroma. ..
- Zhou L, McMahon C, Bhagat T, Alencar C, Yu Y, Fazzari M, et al. Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Cancer Res. 2011;71:955-63 pubmed publisher..b>SMAD7 protein was also found to be significantly decreased in MDS marrow progenitors when examined immunohistochemically in ..
- Loh Y, Mitrou P, Wood A, Luben R, McTaggart A, Khaw K, et al. SMAD7 and MGMT genotype variants and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study. Cancer Epidemiol. 2011;35:369-74 pubmed publisherThe SMAD7 gene was recently identified to be associated with colorectal cancer risk. Smad7 protein is a known inhibitor of TGF-? signalling pathway which has a prominent role in tumorigenesis...
- Miyake T, Alli N, McDermott J. Nuclear function of Smad7 promotes myogenesis. Mol Cell Biol. 2010;30:722-35 pubmed publisher..Thus, Smad7 has a nuclear coactivator function that is independent of TGF-beta signaling and necessary to promote myogenic differentiation. ..
- Yang F, Chung A, Huang X, Lan H. Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and -independent Smad pathways: the role of Smad3. Hypertension. 2009;54:877-84 pubmed publisher..In conclusion, Ang II induces tubular CTGF expression and renal fibrosis via the TGF-beta-dependent and -independent Smad3 signaling pathways, suggesting that targeting Smad3 may have therapeutic potential for hypertensive nephropathy. ..
- Leng A, Liu T, He Y, Li Q, Zhang G. Smad4/Smad7 balance: a role of tumorigenesis in gastric cancer. Exp Mol Pathol. 2009;87:48-53 pubmed publisher..This effect is concentration and time dependent. Thus, this study provides a mechanism by which a balance between Smad4 and Smad7 in human gastric cancer is critical for differentiation, metastasis, and apoptosis of tumor cells. ..
- He J, Sun X, Qian K, Liu X, Wang Z, Chen Y. Protection of cerulein-induced pancreatic fibrosis by pancreas-specific expression of Smad7. Biochim Biophys Acta. 2009;1792:56-60 pubmed publisher..Taken together, these data indicate that inhibition of TGF-beta signaling by Smad7 is able to protect cerulein-induced pancreatic fibrosis in vivo. ..
- Halder S, Rachakonda G, Deane N, Datta P. Smad7 induces hepatic metastasis in colorectal cancer. Br J Cancer. 2008;99:957-65 pubmed publisher..Therefore, this report demonstrates, for the first time, that blockade of TGF-beta/Smad pathway in colon cancer cells induces metastasis, thus supporting an important role of Smad signalling in inhibiting colon cancer metastasis. ..
- Liu F, Li X, Peng Y, Liu H, Liu Y. Arkadia regulates TGF-beta signaling during renal tubular epithelial to mesenchymal cell transition. Kidney Int. 2008;73:588-94 pubmed..their levels of Arkadia, Smurf2, TGF-beta type I receptor (TbetaRI), and Smad7 mRNA, but had low levels of Smad7 protein. When these cells were preincubated with Arkadia siRNA (small interfering RNA) and lactacystin (an inhibitor ..
- Saika S, Yamanaka O, Nishikawa Ishida I, Kitano A, Flanders K, Okada Y, et al. Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse model. Arch Ophthalmol. 2007;125:647-54 pubmed..To determine the effects of Smad7 gene transfer in the prevention of fibrogenic responses by the retinal pigment epithelium, a major cause of proliferative vitreoretinopathy after retinal detachment, in mice...
- Banas M, Parks W, Hudkins K, Banas B, Holdren M, Iyoda M, et al. Localization of TGF-beta signaling intermediates Smad2, 3, 4, and 7 in developing and mature human and mouse kidney. J Histochem Cytochem. 2007;55:275-85 pubmed
- Seyhan H, Hamzavi J, Wiercinska E, Gressner A, Mertens P, Kopp J, et al. Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling. J Cell Mol Med. 2006;10:922-32 pubmed..Further, negative feedback regulation of TGF-beta signaling by increased Smad7 expression in activated hepatic stellate cells occurs, however does not interfere with fibrogenesis. ..