Alternative titles; symbols
HGNC Approved Gene Symbol: SMAD7
Cytogenetic location: 18q21.1 Genomic coordinates (GRCh38): 18:48,919,853-48,950,965 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.1 | {Colorectal cancer, susceptibility to, 3} | 612229 | 3 |
TGF-beta-1 (TGFB1; 190180) is a multifunctional cytokine that regulates growth, differentiation, and function of immune and nonimmune cells via interaction with membrane receptors (e.g., TGFBR1; 190181). These receptors are serine-threonine kinases that phosphorylate and activate intracellular SMAD2 (601366) and SMAD3 (603109), which then interact with SMAD4 (600993) and translocate to the nucleus to regulate nuclear gene expression. SMAD7 is an inhibitory protein that interacts with TGFBR1 and blocks its kinase activity, thereby blocking transduction of TGFB1 signaling (summary by Monteleone et al., 2001).
MAD proteins, originally defined in Drosophila, are essential components of the signaling pathways of the TGFBR family. Using a differential display approach in cultured endothelial cells subjected to multiple soluble and biomechanical stimuli, Topper et al. (1997) isolated a human endothelial cell cDNA encoding MADH7, which they called SMAD7. The predicted 426-amino acid MADH7 protein lacks the C-terminal putative phosphorylation sites present in other MAD proteins, suggesting that it may be distinctly regulated. In situ hybridization and immunohistochemical analyses on human tissues showed that MADH7 is expressed predominantly in vascular endothelium.
By somatic cell hybrid analysis, Topper et al. (1997) mapped the MADH7 gene to human chromosome 18. By FISH, Roijer et al. (1998) refined the localization to chromosome 18q21.1.
Topper et al. (1997) demonstrated that MADH7 and MADH6 (602931) could form complexes in endothelial cells. MADH7 was induced in cultured vascular endothelium by fluid mechanical forces and was capable of modulating endothelial gene expression in response to both humoral and biomechanical stimuli in vitro.
Kavsak et al. (2000) found that the E3 ubiquitin ligase SMURF2 (605532) associates constitutively with SMAD7. SMURF2 is nuclear, but binding to SMAD7 induced export and recruitment to the activated TGFBR, where it caused degradation of receptors and of SMAD7 via proteasomal and lysosomal pathways. Gamma-interferon (IFNG; 147570), which stimulates expression of SMAD7, induced SMAD7-SMURF2 complex formation and increased TGFBR turnover, which was stabilized by blocking SMAD7 or SMURF2 expression. Furthermore, SMAD7 mutants that interfered with recruitment of SMURF2 to the receptors were compromised in their inhibitory activity. These studies defined SMAD7 as an adaptor in an E3 ubiquitin ligase complex that targets TGFBR for degradation.
Lallemand et al. (2001) showed that cells stably expressing SMAD7 had increased susceptibility to apoptosis induced by TGFB, TNFA (191160), serum withdrawal, or loss of cell adhesion (anoikis). SMAD7 decreased NFKB (164011) activity, providing a mechanism for the increased apoptosis. Stable expression of RAS (190020) suppressed SMAD7 inhibition of NFKB and SMAD7 potentiation of apoptosis.
Using Western blot analysis, Monteleone et al. (2001) found that SMAD7 was overexpressed in intestines of patients with Crohn disease and ulcerative colitis (see 266600) compared with normal controls. SMAD7 overexpression was accompanied by reduced SMAD3 phosphorylation and proinflammatory cytokine production. Blockade of SMAD7 in isolated patient mucosal lamina propria mononuclear cells with antisense oligonucleotides restored signaling in response to applied TGFB1 and permitted TGFB1 to inhibit cytokine production. Antagonizing SMAD7 in Crohn disease organ cultures also restored SMAD3 phosphorylation and reduced cytokine production. Monteleone et al. (2001) concluded that inhibition of SMAD7 enables endogenous TGFB1 to downregulate the inflammatory process in inflammatory bowel disease.
Gronroos et al. (2002) presented evidence that SMAD7 interacts with the transcriptional coactivator p300 (602700), resulting in acetylation of SMAD7 on 2 lysine residues in its N terminus. Acetylation or mutation of these lysine residues stabilized SMAD7 and protected it from TGFB-induced degradation. The authors demonstrated that the acetylated residues in SMAD7 also are targeted by ubiquitination and that acetylation of these lysine residues prevents subsequent ubiquitination. Specifically, acetylation of SMAD7 protected it against ubiquitination and degradation mediated by the ubiquitin ligase SMURF1 (605568). The data suggested that competition between ubiquitination and acetylation of overlapping lysine residues constitutes another mechanism to regulate protein stability.
Saika et al. (2007) determined the effects of Smad7 gene transfer in the prevention of fibrogenic responses by the retinal pigment epithelium, a major cause of proliferative vitreoretinopathy (193235) after retinal detachment, in mice using a retinal detachment-induced proliferative vitreoretinopathy mouse model and the retinal pigment epithelial cell line ARPE19. Smad7 gene transfer inhibited TGFB2/Smad signaling in ARPE19 cells and expression of collagen type I and TGFB1, but it had no effect on their basal levels. In vivo, Smad7 overexpression resulted in suppression of Smad2/3 signals and of the fibrogenic response to epithelial-mesenchymal transition by the retinal pigment epithelium. Saika et al. (2007) concluded that Smad7 gene transfer suppressed fibrogenic responses to TGFB2 by retinal pigment epithelial cells in vitro and in vivo.
In a genomewide association study, genotyping 550,163 SNPs in 940 individuals with familial colorectal tumors including 627 with colorectal cancer (CRC; 114500) and 313 with advanced adenomas, and 965 controls, Broderick et al. (2007) identified 3 SNPs in SMAD7 associated with CRC. Across 4 sample sets, the association between rs4939827 (602932.0001) and CRC was highly statistically significant.
Fukasawa et al. (2004) investigated Smad-mediated Tgfb signaling in mice with unilateral ureteral obstruction (UUO), a model of kidney disease with progressive tubulointerstitial fibrosis. The level of Smad7 protein, but not mRNA, decreased progressively in UUO kidneys through ubiquitination and degradation. Expression of Smurf1 and Smurf2, which are E3 ubiquitin ligases for Smad7, increased, and they interacted with Smad7 in UUO kidneys. Fukasawa et al. (2004) concluded that enhanced ubiquitin-dependent degradation of SMAD7 plays a pathogenic role in progression of tubulointerstitial fibrosis.
SMAD7 is expressed at low levels in normal epithelial tissues, but it is overexpressed in some cancers, in inflammatory bowel disease (see 266600), and in progressive glomerulosclerosis in mice. Using a chimeric transcript to drive expression of Smad7 from the keratin-5 (KRT5; 148040) promoter, He et al. (2002) overexpressed Smad7 in the skin of mice. Transgenic mice exhibited severe defects in multiple epithelial tissues, including significantly delayed and aberrant hair follicle formation, marked hyperplasia in the epidermis and other stratified epithelia, aberrant development of the eyelid and cornea, and severe thymic atrophy.
Li et al. (2006) generated mice lacking exon 1 of the Smad7 gene. These mice were viable but smaller than wildtype mice. Mutant mice showed overactive Tgfb signaling, as measured by an increase in Smad2 (601366)-positive B cells. B cells from mutant mice had increased Ig class switch recombination to IgA, enhanced spontaneous apoptosis, and reduced proliferation in response to lipopolysaccharide stimulation.
The article in which Dong et al. (2002) suggested that alterations in the SMAD pathway, including marked SMAD7 deficiency and SMAD3 upregulation, may be responsible for the TGFB1 hyperresponsiveness observed in scleroderma (181750) was retracted because some of the elements in figure 3 may have been fabricated.
The article by Kan et al. (2015), in which the authors concluded that MIR520G (616272) promotes metastasis by downregulating SMAD7 and permitting TGFB signaling, was retracted.
In a large genomewide association study to identify variants that influence risk of colorectal cancer (CRCS3; 612229), Broderick et al. (2007) identified the strongest association with a single-nucleotide polymorphism (SNP) in intron 3 of the SMAD7 gene, rs4939827 (P = 1.0 x 10(-12)). The T allele confers risk.
Tomlinson et al. (2008) and Tenesa et al. (2008) confirmed the association of rs4939827 with risk of colorectal cancer.
Broderick, P., Carvajal-Carmona, L., Pittman, A. M., Webb, E., Howarth, K., Rowan, A., Lubbe, S., Spain, S., Sullivan, K., Fielding, S., Jaeger, E., Vijayakrishnan, J., and 20 others. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nature Genet. 39: 1315-1317, 2007. [PubMed: 17934461] [Full Text: https://doi.org/10.1038/ng.2007.18]
Dong, C., Zhu, S., Wang, T., Yoon, W., Li, Z., Alvarez, R. J., ten Dijke, P., White, B., Wigley, F. M., Goldschmidt-Clermont, P. J. Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc. Nat. Acad. Sci. 99: 3908-3913, 2002. Note: Retraction: Proc. Nat. Acad. Sci. 113: E2208, 2016. [PubMed: 11904440] [Full Text: https://doi.org/10.1073/pnas.062010399]
Fukasawa, H., Yamamoto, T., Togawa, A., Ohashi, N., Fujigaki, Y., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Suzuki, S., Kitagawa, M., Hishida, A. Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice. Proc. Nat. Acad. Sci. 101: 8687-8692, 2004. [PubMed: 15173588] [Full Text: https://doi.org/10.1073/pnas.0400035101]
Gronroos, E., Hellman, U., Heldin, C.-H., Ericsson, J. Control of Smad7 stability by competition between acetylation and ubiquitination. Molec. Cell 10: 483-493, 2002. [PubMed: 12408818] [Full Text: https://doi.org/10.1016/s1097-2765(02)00639-1]
He, W., Li, A. G., Wang, D., Han, S., Zheng, B., Goumans, M.-J., ten Dijke, P., Wang, X.-J. Overexpression of Smad7 results in severe pathological alterations in multiple epithelial tissues. EMBO J. 21: 2580-2590, 2002. [PubMed: 12032071] [Full Text: https://doi.org/10.1093/emboj/21.11.2580]
Kan, H., Guo, W., Huang, Y., Liu, D. MicroRNA-520g induces epithelial-mesenchymal transition and promotes metastasis of hepatocellular carcinoma by targeting SMAD7. FEBS Lett. 589: 102-109, 2015. Note: Retraction: FEBS Lett. 596: 526, 2022; FEBS Open Bio. 12: 549, 2022. [PubMed: 25436421] [Full Text: https://doi.org/10.1016/j.febslet.2014.11.031]
Kavsak, P., Rasmussen, R. K., Causing, C. G., Bonni, S., Zhu, H., Thomsen, G. H., Wrana, J. L. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF-beta receptor for degradation. Molec. Cell 6: 1365-1375, 2000. [PubMed: 11163210] [Full Text: https://doi.org/10.1016/s1097-2765(00)00134-9]
Lallemand, F., Mazars, A., Prunier, C., Bertrand, F., Kornprost, M., Gallea, S., Roman-Roman, S., Cherqui, G., Atfi, A. Smad7 inhibits the survival nuclear factor kappa-B and potentiates apoptosis in epithelial cells. Oncogene 20: 879-884, 2001. [PubMed: 11314022] [Full Text: https://doi.org/10.1038/sj.onc.1204167]
Li, R., Rosendahl, A., Brodin, G., Cheng, A. M., Ahgren, A., Sundquist, C., Kulkarni, S., Pawson, T., Heldin, C.-H., Heuchel, R. L. Deletion of exon I of SMAD7 in mice results in altered B cell responses. J. Immun. 176: 6777-6784, 2006. [PubMed: 16709837] [Full Text: https://doi.org/10.4049/jimmunol.176.11.6777]
Monteleone, G., Kumberova, A., Croft, N. M., McKenzie, C., Steer, H. W., MacDonald, T. T. Blocking Smad7 restores TGF-beta-1 signaling in chronic inflammatory bowel disease. J. Clin. Invest. 108: 601-609, 2001. [PubMed: 11518734] [Full Text: https://doi.org/10.1172/JCI12821]
Roijer, E., Moren, A., ten Dijke, P., Stenman, G. Assignment of the Smad7 gene (MADH7) to human chromosome 18q21.1 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 81: 189-190, 1998. [PubMed: 9730599] [Full Text: https://doi.org/10.1159/000015026]
Saika, S., Yamanaka, O., Nishikawa-Ishida, I., Kitano, A., Flanders, K. C., Okada, Y., Ohnishi, Y., Nakajima, Y., Ikeda, K. Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse model. Arch. Ophthal. 125: 647-654, 2007. [PubMed: 17502504] [Full Text: https://doi.org/10.1001/archopht.125.5.647]
Tenesa, A., Farrington, S. M., Prendergast, J. G. D., Porteous, M. E., Walker, M., Haq, N., Barnetson, R. A., Theodoratou, E., Cetnarskyj, R., Cartwright, N., Semple, C., Clark, A. J., and 45 others. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nature Genet. 40: 631-637, 2008. [PubMed: 18372901] [Full Text: https://doi.org/10.1038/ng.133]
Tomlinson, I. P. M., Webb, E., Carvajal-Carmona, L., Broderick, P., Howarth, K., Pittman, A. M., Spain, S., Lubbe, S., Walther, A., Sullivan, K., Jaeger, E., Fielding, S., and 65 others. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nature Genet. 40: 623-630, 2008. [PubMed: 18372905] [Full Text: https://doi.org/10.1038/ng.111]
Topper, J. N., Cai, J., Qiu, Y., Anderson, K. R., Xu, Y.-Y., Deeds, J. D., Feeley, R., Gimeno, C. J., Woolf, E. A., Tayber, O., Mays, G. G., Sampson, B. A., Schoen, F. J., Gimbrone, M. A., Jr., Falb, D. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc. Nat. Acad. Sci. 94: 9314-9319, 1997. [PubMed: 9256479] [Full Text: https://doi.org/10.1073/pnas.94.17.9314]