Disease relevance of SMAD1

• SMAD signaling may be a mechanism contributing to the characteristic phenotype of scleroderma fibroblasts and playing a role in the pathogenesis of fibrosis [1].
• These results suggest that TGF-beta production by melanoma cells not only affects the tumor environment but also directly contributes to tumor cell aggressiveness through autocrine activation of Smad signaling [2].
• In Smad4-deficient breast cancer cells, TGF-beta failed to modulate Smad expression, suggesting that SMADs mediate their own regulation in response to ligand [3].
• Molecular analyses of the 15q and 18q SMAD genes in pancreatic cancer [4].
• Expression of Smad proteins in human colorectal cancer [5].

Psychiatry related information on SMAD1

• Given that a nuclear localization is required to regulate the transcription of TGF-beta target genes to afford neuroprotection, the ectopic localization of phosphorylated Smad2 suggests a defect in the Smad-mediated signaling pathway of TGF-beta in Alzheimer's disease and consequent loss of neuroprotective function [6].

High impact information on SMAD1

• Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors [7].
• This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners [7].
• E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression [8].
• Smad proteins therefore mediate transcriptional activation or repression depending on their associated partners [8].
• The type I receptor and Smad proteins that are required in vivo for Müllerian duct regression have not yet been identified [9].

Chemical compound and disease context of SMAD1

• CONCLUSIONS: Taken together, these data suggest that quercetin effectively blocks the TGF-beta/Smad-signaling pathway in keloid fibroblasts [10].
• Changes in Smad expression and subcellular localization in bleomycin-induced pulmonary fibrosis [11].
• Our recent studies have demonstrated that Smad signalling is also a critical pathway for renal fibrosis induced by other pro-fibrotic factors, such as angiotensin II and advanced glycation end products (AGE) [12].
• CONCLUSION: The present study suggests that AGE-RAGE-mediated ROS generation activates TGF-beta-Smad signaling and subsequently induces mesangial cell hypertrophy and fibronectin synthesis by autocrine production of Ang II [13].
• These data demonstrate that rebamipide activates Smad signaling pathway and suppresses human gastric cancer cell growth [14].

Biological context of SMAD1

• TSG-deficient thymus was atrophic, and phosphorylation of SMAD1 was augmented in the thymocytes, suggesting enhanced BMP-4 signaling in the thymus [15].
• How distinct Smad complexes regulate specific gene expression is not fully understood [16].
• By 2 hours, TGF-beta induces a marked increase in SnoN expression, resulting in termination of Smad-mediated transactivation [17].
• Smad proteins mediate transforming growth factor-beta (TGF-beta) signaling to regulate cell growth and differentiation [17].
• Bioinformatic analysis of the promoter region of these genes reveals diverse configurations of Smad and FoxO binding elements, implying differences in the regulatory properties of this group of genes [18].

Anatomical context of SMAD1

• Surprisingly, oocytes did not activate the SMAD1/5/8 pathway in transfected GCs although exogenous BMP6 did [19].
• In conclusion, myricetin increased BMP-2 synthesis, and subsequently activated SMAD1/5/8 and p38 MAPK, and this effect may contribute to its action on the induction of osteoblast maturation and differentiation, followed by an increase of bone mass [20].
• We report here that DPC4 is essential for the function of Smad1 and Smad2 in pathways that signal mesoderm induction and patterning in Xenopus embryos, as well as antimitogenic and transcriptional responses in breast epithelial cells [21].
• Transforming growth factor-beta (TGFbeta) regulates the activation state of the endothelium via two opposing type I receptor/Smad pathways [22].
• To delineate the organization of the TGF-beta response in human keratinocytes, we defined the set of genes whose activation by TGF-beta requires both FoxO and Smad functions [18].

Associations of SMAD1 with chemical compounds

• Induction of differentiation by myricetin is associated with increased activation of SMAD1/5/8 and p38 mitogen-activated protein kinases [20].
• Whereas mutations in the C domain disrupt the effector function of the Smad proteins, N-domain arginine mutations inhibit SMAD signalling through a gain of autoinhibitory function [23].
• As a direct physiological substrate of BMP receptors, Smad1 provides a link between receptor serine/threonine kinases and the nucleus [24].
• Smad signaling can be regulated by the Ras/Erk/mitogen-activated protein pathway in response to receptor tyrosine kinase activation and the gamma interferon pathway and also by the functional interaction of Smad2 with Ca(2+)-calmodulin [25].
• Smad proteins are a family of highly conserved, intracellular proteins that signal cellular responses downstream of transforming growth factor-beta (TGF-beta) family serine/threonine kinase receptors [26].
• This study suggests that SSc patients with activated Smad1 signaling may benefit from imatinib mesylate treatment [27].

Physical interactions of SMAD1

• The carboxyl terminus of SNIP1 interacts with Smad1 and Smad2 in yeast two-hybrid as well as in mammalian overexpression systems [28].
• Consistent with the observation that CHIP induces Smad1 degradation, we further show that the expression of CHIP can inhibit the transcriptional activities of the Smad1/Smad4 complex induced by BMP signals [29].
• Smad was identified as a component of the CAGACA-binding transcription complex in TGF-beta-treated fibroblasts by antibody supershifting [30].
• The importance of Smad binding to the CAGACA box of COL1A2 was further established by transcriptional decoy oligonucleotide competition [31].
• Moreover, when expressed in chicken embryo fibroblasts, mutant Ski or SnoN defective in binding to the Smad proteins failed to induce oncogenic transformation [32].

Enzymatic interactions of SMAD1

• Members of the SMAD family of intracellular proteins are phosphorylated by TGF-beta receptors and convey signals to specific TGF-beta-inducible genes [3].
• Smad1 was phosphorylated and underwent nuclear translocation in normal OSE and OC cells upon treatment with BMP4 [33].
• We investigated the mechanism of phosphorylation-induced Smad complex formation with an activating pseudo-phosphorylated Smad3 [34].
• Protein Serine/Threonine Phosphatase PPM1A Dephosphorylates Smad1 in the Bone Morphogenetic Protein Signaling Pathway [35].

Regulatory relationships of SMAD1

• TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300 [36].
• Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation [37].
• c-Ski and SnoN are transcriptional co-repressors that inhibit transforming growth factor-beta signaling through interaction with Smad proteins [38].
• HIPK2 efficiently inhibited Smad1/4-induced transcription from the Smad site-containing promoter [39].
• In fibroblasts, TGFbeta signals through the activin receptor-like kinase 5 (ALK-5) type I TGFbeta and triggers Smad and MAP kinase signaling pathways [40].
• Disruption of microtubule networks by nocodazole activates Mps1 and promotes TGF-beta-independent activation of Smad signaling [41].

Other interactions of SMAD1

• Microinjection of Smad1 messenger RNA into Xenopus embryo animal caps mimics the mesoderm-ventralizing effects of BMP4 [42].
• Smads regulate transcription of defined genes in response to TGF-beta receptor activation, although the mechanisms of Smad-mediated transcription are not well understood [43].
• Binding of both TFE3 and the Smad proteins to their cognate sequences is indispensable for TGF-beta-inducible activation of the PE2 promoter [44].
• Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase [37].
• MDM2 and MDMX inhibit the transcriptional activity of ectopically expressed SMAD proteins [45].

Analytical, diagnostic and therapeutic context of SMAD1

• Transforming growth factor-beta signal transducer SMAD2 but not SMAD1 moved from the cytoplasm to the nucleus after TGF-beta stimulation [46].
• Here we report a novel mechanism of the regulation of SMAD-mediated signaling, by which the Smad1 protein level is controlled through expression of the CHIP protein [29].
• METHODS: Ligand-induced activation of the Smad signaling pathway in human dermal fibroblasts was examined by Western blot analysis and confocal immunocytochemistry [40].
• Electrophoretic mobility shift assays indicate that the AR ligand binding domain directly inhibits the association of Smad3 to the Smad-binding element [47].
• Intracellular compartmentalization of cellular SMAD proteins in the presence and absence of TGFbeta was studied by antibody-mediated immunofluorescence confocal microscopy [1].

References