Disease relevance of Smad1

• Smad6 transgenic mice showed postnatal dwarfism with osteopenia and inhibition of Smad1/5/8 phosphorylation in chondrocytes [1].
• Although no mutations were detected in the Smad2 and -4 genes in tumors, proteins of Smad1 through -5 were partially or completely lost in carcinomas [2].
• Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction [3].
• Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation [4].
• Our studies suggest a new paradigm for amplification of Smad-mediated signaling by an oncoprotein and suggest that enhanced Smad-mediated signaling may contribute to HBV-associated liver fibrosis [5].

High impact information on Smad1

• Smad proteins activated by TGF-beta form a complex with FoxO proteins to turn on the growth inhibitory gene p21Cip1 [4].
• Smad proteins transmit TGFbeta signals from the cell surface to the nucleus [6].
• Most ligands of the family signal through transmembrane serine/threonine kinase receptors and SMAD proteins to regulate cellular functions [7].
• These results underscore the need to tightly balance BMP and MAPK signaling pathways through Smad1 [8].
• Smad1(C/C) mutants recapitulate many Smad1(-/-) phenotypes, including defective allantois formation and the lack of primordial germ cells (PGC), but also show phenotypes that are both more severe (head and branchial arches) and less severe (allantois growth) than the null [8].

Chemical compound and disease context of Smad1

• We concluded that the TGF-beta1/Smad signaling pathway helps maintain normal intestinal homeostasis to commensal luminal enteric bacteria by regulating NF-kappaB signaling in IEC through altered histone acetylation [9].
• Inhibitory effect of genistein on mouse colon cancer MC-26 cells involved TGF-beta1/Smad pathway [10].
• CONCLUSIONS: It appears that candesartan reduced urinary type IV collagen and albumin excretion, and attenuated glomerular hypertrophy and mesangial matrix accumulation by the TGF-betaS/Smad signaling pathway in KK/Ta mice with diabetic nephropathy [11].
• METHODS: Recombinant adenoviruses expressing either green fluorescent protein or a transforming growth factor beta/Smad signal repressor, YB-1, were injected into mice untreated or treated with carbon tetrachloride [12].

Biological context of Smad1

• Smooth muscle differentiation requires BMP-mediated Smad1/5/8 activation and predominates where local cell density is low [13].
• Although Smad8(Deltaexon3/Deltaexon3) embryos are phenotypically normal, homozygotes of another hypomorphic allele of Smad8 (Smad8(3loxP)) containing a neomycin cassette within intron 3, phenocopy an embryonic brain defect observed in roughly 22% of Smad1(+/)(-) embryos analyzed at embryonic day 11 [14].
• The cardiac determination factor, Nkx2-5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer [15].
• We conclude that BMP7 stimulates renal epithelial cell morphogenesis via p38(MAPK) and that p38(MAPK) activity is negatively regulated by Smad1 [16].
• Osteoblast differentiation and bone formation is stimulated by bone morphogenetic protein (BMP)-2 and its downstream signaling molecules Smad1 and -5 and the osteoblast-specific transcription factor core-binding factor alpha1 (Cbfa1) [17].

Anatomical context of Smad1

• Previous research has shown that Smad1 is important in the formation of the allantois, while Smad5 has been shown to be critical in the process of angiogenesis [14].
• Smad1 and Smad8 function similarly in mammalian central nervous system development [14].
• These data indicate that menin inactivation specifically inhibits the commitment of pluripotent mesenchymal stem cells to the osteoblast lineage, mediated by menin and Smad1/5 interactions [18].
• We sought to map transcriptional Smad1/5 activity in development by generating embryonic stem cell lines carrying a Smad1/5-specific response element derived from the Id1 promoter coupled to beta-galactosidase or luciferase as reporters [19].
• At the protein level, Smad1 was detected throughout the epidermis, whereas Smad2 through -5 exhibited greater levels in suprabasal layers than basal keratinocytes [2].

Associations of Smad1 with chemical compounds

• SB202190, a p38 mitogen-activated protein kinase inhibitor, inhibited this effect of BMP-7; however, since SB202190 suppressed phosphorylation of Smad1/5, this may be due to blockade of BMP receptor activation [20].
• The biological effects of type I serine/threonine kinase receptors and Smad proteins were examined using an adenovirus-based vector system [21].
• Low-level bisphenol A increases production of glial fibrillary acidic protein in differentiating astrocyte progenitor cells through excessive STAT3 and Smad1 activation [22].
• We have studied the effects of two new synthetic triterpenoids, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivative, 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im), on transforming growth factor (TGF)-beta/Smad signaling [23].
• Together these data provide the first evidence that activation of BMP receptor serine/threonine kinase stimulates the PI 3 kinase/Akt pathway and define a role for this signal transduction pathway in BMP-specific Smad function during osteoblast differentiation [24].

Physical interactions of Smad1

• SMAD 8 binding to mice Msx1 basal promoter is required for transcriptional activation [25].
• 2. Furthermore, the recruitment of an HDAC/Sin3A complex to Nkx3.2 requires that Nkx3.2 interact with Smad1 and -4 [26].
• Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells [27].
• In this study we tested the hypothesis that a putative Smad-binding region containing the sequence AGACTGTCTGGAC is involved in the activation of the OPN promoter by members of the TGFbeta superfamily [28].
• For instance, in fetal brain, it has been shown that the neurogenic transcription factor Neurogenin1 inhibits formation of a STAT3/p300/ Smad1 complex and that the oligodendrocytic transcription factor OLIG2 does the same [29].

Enzymatic interactions of Smad1

• We also found that BMP4-induced differentiation of PGCs from epiblast in vitro was fully dependent on the existence of phosphorylated SMAD1 [30].
• Endogenous Smad pathway was activated in the obstructed kidney after UUO in wild-type mice as judged by the increase of phosphorylated Smad2 or phosphorylated Smad2/3-positive cells in renal interstitial area [31].
• TGF-beta signaling is transduced from the cell membrane to the nucleus by means of specific type I and type II receptors and phosphorylated Smad proteins [32].

Co-localisations of Smad1

• CIZ/Nmp4 was co-localized with Smad1 in the testis, suggesting that a disregulation of BMP signalling could cause these phenotypes [33].

Regulatory relationships of Smad1

• Smurf1 has been found to interact with BMP-activated Smad1 and -5 and to mediate degradation of these Smad proteins [34].
• However, Smad does not directly induce Runx2 expression; an additional step of de novo protein synthesis is required [35].
• BMP-induced Smad1 and Smad5 activation of GCCG-mediated transcription was blocked in the presence of CIZ overexpression [36].
• BMP-4 triggered the phosphorylation of Smad1, suggesting that the effect of BMP-4 on FSH secretion is due to the activation of the BMPs signaling pathway [37].
• Transcripts of Smad1 through -5 were constantly expressed in the epidermis regardless of changes in TGFbeta signaling, state of differentiation and stages of carcinogenesis [2].

Other interactions of Smad1

• p38MAPK acts in the BMP7-dependent stimulatory pathway during epithelial cell morphogenesis and is regulated by Smad1 [16].
• This increase is probably due to the activation of the gene encoding 204 (Ifi204) by Smad transcription factor, including Smad1, -4, and -5 [38].
• Here we report that Smad-induced junB functions as an upstream activator of Runx2 expression [35].
• During skin carcinogenesis, loss of Smad1 through -5 and overexpression of Smad7 may contribute to the loss of growth inhibition mediated by TGFbeta superfamily members, thus resulting in tumor progression [2].
• The bone morphogenetic protein 2 signaling mediator Smad1 participates predominantly in osteogenic and not in chondrogenic differentiation in mesenchymal progenitors C3H10T1/2 [39].
• Taken together, miR-199a(*) is the first BMP2 responsive microRNA found to adversely regulate early chondrocyte differentiation via direct targeting of the Smad1 transcription factor [40].

Analytical, diagnostic and therapeutic context of Smad1

• This composite Nkx2-5 enhancer was a direct target of BMP signaling via cooperative interactions between the downstream transducers Smad1/4 and GATA-4 [15].
• Most of the Smad1-/- embryos contained no primordial germ cells (PGCs) and had short allantois, while histological analysis and in situ hybridization for the mesoderm marker genes revealed that early mesoderm induction was normal in those embryos [30].
• Phosphorylation of mothers against decapentaplegic homolog 1 (Smad1) and bone morphogenetic protein (BMP)-like molecules in EMD was determined by Western blot [41].
• A proteomic analysis of the complex components after immunoprecipitation identified several proteins necessary to activate transcription including SMAD 8 [25].
• Transfection assays in cell cultures with fragments from BP driving the expression of luciferase confirmed that only in the presence of the SMAD consensus site is Msx1 expression activated [25].

References