Disease relevance of SMAD7

• Combined copy status of 18q21 genes in colorectal cancer shows frequent retention of SMAD7 [1].
• Ultraviolet A1 phototherapy decreases inhibitory SMAD7 gene expression in localized scleroderma [2].
• Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring [3].
• Smad7 is overexpressed in 50% of human pancreatic cancers [4].
• Smad7 abrogates transforming growth factor-beta1-mediated growth inhibition in COLO-357 cells through functional inactivation of the retinoblastoma protein [4].

High impact information on SMAD7

• Smad7 interacts stably with the activated TGFbeta type I receptor, thereby blocking the association, phosphorylation, and activation of Smad2 [5].
• Specifically, acetylation of Smad7 protects it against ubiquitination and degradation mediated by the ubiquitin ligase Smurf1 [6].
• Control of Smad7 stability by competition between acetylation and ubiquitination [6].
• These studies thus define Smad7 as an adaptor in an E3 ubiquitin-ligase complex that targets the TGF beta receptor for degradation [7].
• Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7 [7].

Chemical compound and disease context of SMAD7

• COLO-357 pancreatic cancer cells engineered to overexpress Smad7 are resistant to the actions of transforming growth factor-beta1 (TGF-beta1) with respect to growth inhibition and cisplatin-induced apoptosis but not with respect to modulation of gene expression [4].
• 2-Methoxyestradiol-induced apoptosis in prostate cancer cells requires Smad7 [8].
• In contrast, blockade of Smad2/3 activation by overexpression of an inhibitory Smad7 prevents collagen matrix production induced by TGF-beta, angiotensin II, high glucose and AGE and attenuates renal fibrosis in various animal models including rat obstructive kidney, remnant kidney and diabetic kidney diseases [9].
• Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice [10].
• RESULTS: Compared with the hepatic fibrosis models, the levels of TGF-beta1, TRII mRNA and the expression Smad3 significantly decreased in the two treated groups, and the expression of Smad7 was significantly increased in the liver of rats treated with perindopril or valsartan (P < 0.05 or P < 0.01) [11].

Biological context of SMAD7

• A -303 to +672 SMAD7 region contained a palindromic GTCTAGAC Smad binding element (SBE) between nucleotides -179 and -172 that was necessary for the induction of a Smad7 promoter luciferase reporter gene by TGF-beta [12].
• To define the molecular mechanisms of negative control of TGF-beta signaling, we have isolated the human SMAD7 gene and characterized its promoter region [12].
• Some epithelia were transfected with an expression plasmid encoding SMAD7 to block TGF-beta-SMAD signaling [13].
• Unexpectedly, we found some gene duplications; SMAD7 appears to be more frequently amplified (10%) than the three other genes (4-7%) [1].
• Moreover, the HRs associated with one additional copy of SMAD7 were 1.76, p = 0.00024 [OS] and 1.64, p = 0.00048 [DFS] respectively, showing a graded effect of SMAD7 on patient outcome depending on gene copy number that suggests a dose-and-effect basis [14].

Anatomical context of SMAD7

• Abrogation of transforming growth factor-beta signaling by SMAD7 inhibits collagen gel contraction of human dermal fibroblasts [15].
• Modulation of proliferation-specific and differentiation-specific markers in human keratinocytes by SMAD7 [16].
• The ability of SMAD7 to suppress cdc2 promoter activity was lost in transformed keratinocyte cell lines and was mediated by a domain(s) located between aa 195-395 of SMAD7 [16].
• Smad7 expression is increased in rat prostatic epithelial cells undergoing apoptosis as a result of castration [2] [17].
• Basal and suprabasal cell layers in erythematous oral lichen showed strong cytoplasmic Smad7 protein staining, but in spinous and granular layers Smad7 was localized to the cell membrane [18].

Associations of SMAD7 with chemical compounds

• Correspondingly, Smad7 bound poorly to a mutant ALK-4 bearing serine to alanine substitutions in four putative phosphorylation sites in its GS domain [19].
• Finally, N-acetylcysteine, TGF-beta antibody, Smad7, and dominant-negative Smad3 reversed beta-HB (1 mmol/L)-induced growth inhibition at 48 hours [20].
• The regulating role of Smad signaling in high glucose-induced collagen synthesis was determined by inducing overexpression of the inhibitory Smad7 in a stable Smad7-expressing tubular cell line [21].
• CONCLUSION: The data show that SB-202190 and SB-203580 suppress TGFbeta-dependent activation of genes that are important for the acquisition of invasive behavior, while having no effect on the expression of the natural TGFbeta inhibitor Smad7 [22].
• METHODS: Alpha-smooth muscle actin (alpha-SMA), Smad2/3, and Smad7 protein were assessed by Western blot [23].

Physical interactions of SMAD7

• Deletion of the AP-1 binding site in the Smad7 promoter completely abolished UV stimulation of SMAD7 transcription [24].
• In this report, we show that TGF-beta can stabilize Smad7 mRNA and activate Smad7 transcription [25].
• We demonstrate that on TGF-beta treatment, endogenous SMAD complex can bind to a Smad7 promoter DNA as short as 14 or 16 bp that contains the 8-bp SBE in gel mobility shift and supershift assays [25].
• Ski along with Smad4 binds and represses the smad7 promoter, whereas the repression mechanism by SnoN is not clear [26].
• SnoN co-repressor binds and represses smad7 gene promoter [26].
• The SRF binding domain of Smad7 mapped to the C-terminal half of the Smad7 molecule [27].

Co-localisations of SMAD7

• Smad4 co-localized with Smad7 and Smurf1 primarily in the cytoplasm and in peripheral cell protrusions [28].

Regulatory relationships of SMAD7

• Furthermore, TGF-beta1-induced apoptosis was prevented by inhibition of Smad7 expression, by antisense mRNA in stably transfected cell lines or upon transient transfection with antisense oligonucleotides in several investigated cell lines [17].
• Activation of endogenous NF-kappaB by tumour necrosis factor-alpha (TNF-alpha) was also able to inhibit the Smad7 promoter in human embryonic kidney 293 cells [29].
• This Smad7 inhibition is enhanced by co-expression of Smurf1 [30].
• Further, Smad7 expression inhibited alpha1 (I) collagen and alpha-smooth muscle actin expression [15].
• These results suggest that the myostatin signal transduction pathway is regulated by Smad7 through a negative feedback mechanism [30].
• Our findings suggest that Smad7 inhibits TGF-beta signaling in the nucleus by a novel mechanism [31].

Other interactions of SMAD7

• Here we demonstrate that STRAP synergizes specifically with Smad7, but not with Smad6, in the inhibition of TGF-beta-induced transcriptional responses [32].
• These findings provide evidence for a new effector function for Smad7 in TGF-beta1 signaling [17].
• 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 [33].
• These data demonstrate that induction of Smad7 gene expression by UV irradiation is mediated via induction of the transcription factor AP-1 in human skin fibroblasts [24].
• In situ immunostaining showed that most epithelial cells in normal oral mucosa had nuclear and cytoplasmic Smad4 and phosphorylated Smad2/3, but expressed little or no Smad7 [18].

Analytical, diagnostic and therapeutic context of SMAD7

• In contrast to SMAD2 deletion, for which no clinical relevance was observed, hazard ratios (HR) in a multivariate analysis associated with SMAD7 deletion [overall survival (OS): HR = 0.43, p = 0.0012; disease-free survival (DFS): HR = 0.50, p = 0.0033] indicated a favorable outcome for these patients [14].
• Inhibitory SMAD7 mRNA was significantly higher in lesional skin as compared to unaffected skin, and significantly decreased after UVA1 phototherapy [2].
• We now report that Smad7 mRNA levels are increased in human pancreatic cancer by comparison with the normal pancreas, and that by in situ hybridization, Smad7 is over-expressed in the cancer cells within the tumor mass [34].
• Collectively, these data show that the Tregs that mediate col(V)-induced tolerance to lung allografts do not express SMAD7 and, therefore, are permissive to TGF-beta-mediated signaling [35].
• Immunofluorescence analysis revealed that the inhibitory Smad, Smad7, was exported to the cytoplasm from the nucleus by the treatment with Ac-SDKP [36].

References