Disease relevance of Smad7

• Our results suggest that the reduction of Smad7 protein resulting from enhanced ubiquitin-dependent degradation plays a pathogenic role in progression of tubulointerstitial fibrosis [1].
• C57BL/6 mice with bleomycin-induced lungs received an intratracheal injection of a recombinant adenovirus carrying mice Smad7 cDNA [2].
• 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 [3].
• Background & Aims: Defective transforming growth factor (TGF)-beta1 signaling due to high levels of Smad7 is a feature of inflammatory bowel disease (IBD) [3].
• Further, constitutive expression of exogenous Smad7 potently enhanced skeletal muscle differentiation and cellular hypertrophy [4].

High impact information on Smad7

• The antagonism is mediated through up-regulation of Smad7 synthesis and induction of stable associations between ligand-activated TGF-beta receptors and inhibitory Smad7 [5].
• To address this issue, we developed transgenic mice expressing Smad7, an intracellular antagonist of TGF-beta/Smad signaling, selectively in mature T cells using a plasmid construct coding a promoter element (the distal lck promoter) that directs high expression in peripheral T cells [6].
• To determine the functions of Smad7, we have expressed Smad7 in transgenic mice, utilizing a keratin K5 promoter (K5.Smad7) [7].
• Our study provides evidence that Smad7 is a potent in vivo inhibitor for signal transduction of the TGFbeta superfamily during development and maintenance of homeostasis of multiple epithelial tissues [7].
• Compared with sham-operated kidneys, the level of Smad7 protein, but not mRNA, decreased progressively in UUO kidneys, whereas immunoreactivity for nuclear phosphorylated Smad2 and Smad3 and renal fibrosis were inversely increased [1].

Biological context of Smad7

• Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice [1].
• Attenuation of Smad2 gene expression resulted in significant advancement of embryonic tooth development with increased proliferation of enamel organ epithelial cells, while attenuation of Smad7 resulted in significant inhibition of embryonic tooth development with increased apoptotic activity within enamel organ epithelium [8].
• To characterize the regulation of Smad7 at the transcriptional level, we isolated the promoter region of the mouse Smad7 gene [9].
• Transfection of Smad7, an inhibitory Smad, also significantly inhibited TGF-beta1-induced apoptosis of these cells [10].
• While TGFbeta1 signal transduction occurs in megakaryocytes in untreated bone marrows, it is inhibited in megakaryocytes in amifostine-treated marrows due to the induction of smad 7 activation [11].

Anatomical context of Smad7

• The inhibitory effect of Smad7 on adipocyte differentiation and its cooperation with TGF-beta was associated with the C-domain of Smad7 [12].
• Although acceleration of healing of the burned cornea was also observed in mice lacking Smad3, the effects on epithelial and stromal healing were less pronounced than those in corneas treated with Smad7 [13].
• Despite apparent activation of the intracellular transforming growth factor-beta signaling pathway in the lesional dermis, the expression of transforming growth factor-beta-inducible Smad7 was not upregulated [14].
• In contrast, Smad6 was selectively expressed at high levels, e.g. in intramembranous bone whereas Smad7 was prominent in seminiferous tubules of the testis, demonstrating distinct expression of these genes in non-cardiovascular tissues [15].
• Immunohistochemistry evaluation showed a significant increase of CD3+ T cell, TGF-beta1 and Smad7 staining in the small and large intestine mucosa of Smad3 null mice as compared to wild-type mice [16].

Associations of Smad7 with chemical compounds

• The degradation of p57(Kip2) evoked by TGF-beta1 was blocked by forced expression of an inhibitory Smad called Smad7 or by the addition of actinomycin D or alpha-amanitin [17].
• Expression of Smad7, the endogenous inhibitor of transforming growth factor-beta/Smad signaling, was strongly induced in dermal cells by transforming growth factor-beta, but not by bleomycin injections [14].
• Smad7 immunoexpression was detected in the cytoplasm of megakaryocytes in the non-irradiated, amifostine-treated and in the irradiated, amifostine-treated marrows [11].
• We have identified serine 249 in Smad7 as a major phosphorylation site, the phosphorylation of which was not affected by TGF-beta1 [18].
• By using adenoviral vector, we demonstrated that Smad7 overexpression attenuated genistein-induced growth inhibition and apoptosis as determined by MTT and apoptosis ELISA [19].
• Our data therefore indicate that the function of alpha3beta1 integrin as a mediator of keratinocyte migration is not essential for reepithelialization but suggest instead that alpha3beta1 integrin has a major new in vivo role as an inhibitor of Smad7 during wound healing [20].

Physical interactions of Smad7

• Finally, we document that Smad7 directly interacts with MyoD and enhances MyoD transcriptional activity [4].

Regulatory relationships of Smad7

• Increased Smad6 and Smad7 levels blocked differentiation and enhanced TGF-beta-induced responses [12].
• Overexpressed Smad7 also prevented ligand-induced PI3 kinase activity [21].
• Moreover, we found that Smad6 and Smad7 suppressed GDF-5-induced apoptosis in HS-72 cells [22].
• Our data provide in vivo evidence for distinct effects of Smad7 at different stages during chondrocyte differentiation and suggest that Smad7 in prechondrogenic cells inhibits chondrocyte differentiation possibly by down-regulating BMP-activated p38 MAPK pathways [23].

Other interactions of Smad7

• COL1A2 promoter activity was dose dependently induced by TGF-beta1, which was further augmented by adenoviral overexpression of Smad3, but was downregulated by Smad7 [24].
• Taken together, our data imply that Smads, together with activator protein-1 and Sp1 transcription factors, are essential for efficient Smad7 promoter activity [25].
• PP1alpha interacted with ALK1 and this association was further potentiated by Smad7 [26].
• To assess the involvement of intracellular signaling protein Smads in regulating goldfish FSHbeta promoter, we first cloned full-length cDNAs for goldfish Smad2, Smad3, Smad4, and Smad7 from the pituitary [27].
• Quantitative polymerase chain reaction was performed for CTGF, Smad3, and Smad7 expression [28].
• TGFbeta failed to induce apoptosis in Smad7 knockdown mesangial cells, indicating that Smad7 mainly mediates TGFbeta-induced apoptosis of mesangial cells [29].
• We conclude that Smad7 mediates a protective effect from adverse TGF-beta signalling in damaged liver, re-iterating its negative regulatory loop on signalling [30].

Analytical, diagnostic and therapeutic context of Smad7

• Smad3 and -4 were found in nuclei of normal corneal epithelium, whereas they were absent in nuclei of migrating cells in association with Smad7 upregulation on epithelial debridement [31].
• Oral administration of Smad7 antisense oligonucleotide to colitic mice restored TGF-beta1 signaling via Smad3 and ameliorated inflammation in hapten-induced colitis [3].
• We also demonstrate by transient transgenesis that overexpression of Smad7 in mouse zygotes inhibits development beyond the 2-cell stage [32].
• Lens epithelial cells in the Cre adv control group exhibited a fibroblastic appearance at days 5 and 10 and the capsular break was sealed with fibrous tissue, while Smad7 adv-treated cells around the capsular break retained their epithelial morphology and the break was not sealed [33].
• CONCLUSIONS: Smad7 gene transfer modulates injury-induced wound healing of conjunctival tissue in mice, suggesting that this strategy may be effective in preventing excessive scarring following filtration surgery [34].

References