Database for Annotation, Visualization and Integrated Discovery 2.1
National Institute of Allergy and Infectious Disease
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SMAD family member 4(SMAD4) SMAD family member 4(SMAD4) Related Genes Homo sapiens
CHROMOSOME 18,
CYTOBAND 18q21.1,
ENSEMBL_GENE_ID ENSG00000141646,
GENERIF_SUMMARY DNA-binding protein, Alterations in tumor-suppressor gene DPC4 may play an important role during the tumorigenesis of pancreatic cancer., A point mutation in Smad4 abolished binding to SMIF., smad4 may play an important role in the regulation of TGFbeta inducible gene expression and subsequent growth inhibition., Common deletion of SMAD4 in juvenile polyposis is a mutational hotspot., TLV-1 tax represses Smad-mediated TGF-beta signaling., Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity., In this study, the expression of Smad4 protein appeared to be correlated with the depth of invasion of esophageal SCC, interactions between AR, Smad3, and Smad4 may result in the differential regulation of the AR transactivation, which further strengthens their roles in the prostate cancer progression, Restoration of transforming growth factor Beta signaling by functional expression of smad4 induces anoikis., determined the crystal structure of a complex between a conserved Smad4 binding fragment of Ski and the MH2 domain of Smad4 at 2.85 A resolution, Smad4/DPC4 has a role in TGF-beta-mediated inhibition of cell proliferation in vitro and in vivo, Phenotypic and functional changes associated with TGF-beta1-induced fibroblast terminal differentiation are differentially regulated by Smad2, Smad3, and Smad4., the re-expression of the Smad4 gene by either method partially restored TGF-beta responsiveness in FaDu cells with respect to both growth inhibition and expression of p21WAF1/CIP1 and p15INK4B, Smad4 point mutations are prevalent in pancreatic carcinoma, they are infrequent in early stages (I-III) of colorectal cancer., Interaction domains of Smad4 and ERalpha are mapped and shown to be essential for transcriptional repression of ERalpha by Smad4., Smad4 is not required for nuclear translocation of Smad2 and Smad3, but is needed for activation of at least certain transcriptional responses., Results suggest that the transcriptional cross talk between the TGFbeta-regulated Smads 3 and 4 and hepatocyte nuclear factor-4 is mediated by specific functional domains in the two types of transcription factors., Human HCC transfectants express a mutant Smad2(3S-A). Serine residues of SSXS motif were changed to alanine. They have impaired Smad2 signaling. Forced expression of Smad2(3S-A induced TGFB secretion & resistance to TGFB-induced growth inhibition., results suggest carcinogenesis in the biliary tract epithelium in anomalous pancreaticobiliary ductal union (APBDU) is accompanied by multistep mutational events; inactivation of DPC-4 gene accumulates late in progression of biliary tract adenocarcinoma, Smad4 is sumoylated and has a role in the regulation of TGF-beta signaling through Smads, Smad-4 had no effect on the basal activity of the MCP-1 promoter, but showed the ability to decrease both Smad-3 and Tat-induced transcription of the MCP promoter in human astrocytic cells, oligo-ubiquitination positively regulates Smad4 function, whereas poly-ubiquitination primarily occurs in unstable cancer mutants and leads to protein degradation, duration of TGF-beta-Smad signaling is a critical determinant of the specificity of the TGF-beta response., SUMO-1 modification serves to protect Smad4 from ubiquitin-dependent degradation and consequently enhances the growth inhibitory and transcriptional responses of Smad4., A G/A transition at 31 bp upstream-nontranslated regions of exon 8 of Smad 4 was found in cervical cancer cells, highlighting an important role for Smad 4 in human cervical tumors., Smad4 interaction with CAN/Nup214, and nuclear import requires structural elements present only in the full-length Smad4; Smad3 and Smad4 have different susceptibility to inhibition of import by cytoplasmic retention factor SARA, Smad4 was expressed in all thyroid cell lines and controls analyzed, differently from other classes of tumors where Smad4 expression was deleted., Sumoylation of Smad4 mainly occurs at lysine 159 and facilitates Smad-dependent transcriptional activation; PIAS-mediated sumoylation of Smad4 is regulated by the p38 MAP kinase pathway, DACH1 bound to endogenous NCoR and Smad4 in cultured cells; Smad4 was required for DACH1 repression of TGF-beta induction of Smad signaling, Smad2, Smad3 and Smad4 contribute to the regulation of TGF-beta responses to varying extents, and exhibit distinct roles in different cell types, Inactivation of DPC4 gene late in neoplastic progression of pancreatic carcinoma. Variation of DPC4 gene activation in biliary tract carcinoma. Common bile duct carcinoma and pancreatic carcinoma have similar molecular alternations., SMAD3 and SMAD4 activate gadd45beta through its third intron to facilitate G2 progression following TGFbeta treatment, DPC4/Smad4 inactivation by mutation or deletion appears to be very rare in pancreatic endocrine tumors., Mutations in SMAD4 abrogate its function in transducing the signaling of TGF-beta, which plays an important role in various stages of cancer formation., DPC4 mutations in appendiceal adenocarcinomas suggests involvement of DPC4 and nearby genes on chromosome 18q (DCC and/or JV-18) in the pathogenesis of appendiceal adenocarcinomas, DPC4 is involved in the development of pancreatic carcinoma and is a late event in pancreatic carcinogenesis., DLX1 is expressed in hematopoietic cells in a lineage-dependent manner and that DLX1 interacts with Smad4 through its homeodomain, CHIP can interact with the Smad1/Smad4 proteins and block BMP signal transduction through the ubiquitin-mediated degradation of Smad proteins., Two missense mutations in the C-terminal domain of Smad4, D351H (Asp351-->His) & D537Y (Asp537-->Tyr), from colorectal cancer cells cannot interact with either TGF-beta-induced phosphorylated Smad2 or Smad3., SMAD4 has a role in regulation of large-scale chromatin unfolding, Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1, Homozygous deletion, followed by inactivating nonsense or frameshift mutations, is the predominant form of MADH4 inactivation in pancreatic cancers., Smad4 showed most significant prognostic differences in stage I gastric cancer patients., decreased nuclear Smad4 expression associated with progression to prostate cancer; loss of BMP2 and Smad4 related to progression to a more aggressive phenotype, Inactivation of the DPC4 gene contributes to the genesis of colorectal carcinoma through allelic loss, Thirty-eight colon carcinomas were analyzed by immunohistochemistry for cell adhesion molecules (E-cadherin, beta-catenin, CD44), cell cycle regulatory proteins (cyclin D1, p27, p21), mismatch repair proteins (hMLH1, hMSH2), cyclooxygenase-2 and DPC4, exon 2 (belonging to the MH1 domain) and exons 8, 10, 11 (belonging to the MH2 domain) are not altered in renal cell carcinoma, a significant role of impaired SMAD4 function in the pathogenesis of small intestinal adenocarcinomas, The most transcriptionally active splice variants of Smad4 are made in macrophages (but not SMCs) of fibrofatty lesions and are upregulated after cell differentiation from monocytes. Cyclin inhibitors are induced by Smads. Fibrous plaque SMCs make Smad4., Dpc4 may have a role in invasiveness of intraductal carcinoma, Our findings suggest that BAMBI transcription is regulated by TGF-beta signaling through direct binding of SMAD3 and SMAD4 to the BAMBI promoter., Regulated cytoplasmic and nuclear retention may play a role in determining the distribution of Smads between the cytoplasm and the nucleus in both uninduced cells and upon TGF-beta induction., DPC4 mutations were found in 40% of pancreatic adenocarcinoma cell lines and 58% of primary tumors. They were mostly deletions in exons 8-11, and 1 frameshift in exon 9., Squamous cell cervical cancer showed loss of Smad4 protein expression or reduced expression., gene expression regulation by TGF beta under Smad4 knockdown, Daxx suppresses Smad4-mediated transcriptional activity by direct interaction with the sumoylated Smad4 and has a role in regulating transforming growth factor beta signaling, expression of Smad4 was significantly lower in diffuse-type gastric adenocarcinoma than intestinal-type gastric adenocarcinomas, TGF-beta signaling suppresses nuclear export of Smad4 by chromosome region maintenance 1 and targets Smad4 into the nucleus; mutations in Smad4 that affect its interaction with Smad2 or Smad3 impair nuclear accumulation of Smad4 in response to TGF-beta, The level of expression of SMAD4 was found to be a more sensitive marker than 18q21 allelic imbalance and SMAD4 mutations, which were of no prognostic significance for colorectal cancer patients., Smad4 is targeted for degradation by multiple ubiquitin ligases that can simultaneously act on R-Smads and signaling receptors, DPC4 inactivation was found in 75% of patients examined for lethal metastatic pancreatic neoplasms., Cancer cell lines harboring Smad4 point mutations exhibited rapid Smad4 protein degradation due to the effect of SCF(beta-TrCP1)., Results suggest that loss of Smad4 expression may be involved in HPV16-induced carcinogenesis of head and neck squamous cell carcinomas., Tsc-22 binds to and modulate the transcriptional activity of Smad3 and Smad4, demonstrate that Smad4 induces apoptosis by regulating Bim splicing as an initial intrinsic signal in ERalpha-positive cells, Smad4 is both frequently mutated and deregulated by aberrant splicing in thyroid tumours and these alterations may contribute as an early event to thyroid tumorigenesis., SMAD4 gene alteration was found in patients, diagnosed with multiploid colorectal carcinomas., There are two populations of TGF-beta target genes that are distinguished by their dependency on Smad4., Smad4, but not Smad2, mediates TGF-beta1-induced MMP-2 expression in invasive extravillous trophoblasts, Functional evidence was provided for a switch of the Smad4 pathway, from tumor-suppressor to prometastatic, in the development of breast cancer bone metastasis., deletion constructs of the promoter and mutational deletion of specific transcription factor binding sites indicated that Smad3/4 and AP-1 binding sites mediated the TGF-beta1 response on LTBP-3, Smad4 plays the role in the transcriptional activation of NF-kappaB., A nonsense mutation of the SMAD4 gene in exon 5 codon 245 CAG (glut) -->TAG (stop) was found in neck squamous cell carcinoma cell line CAL27., Hereditary haemorrhagic telangiectasia and juvenile polyposis in patients with SMAD4 mutations., Biallelic inactivation of SMAD4 through homozygous deletion in breast cancer cell lines and invasive ductal carcinomas.(, One mechanism for positive regulation of TLR2 induction involves functional cooperation between the TGF-betaR-Smad3/4 pathway and NF-kappaB pathway. Another involves (MKP-1)-dependent inhibition of p38 MAPK, a known negative regulator for TLR2 induction, These data define the expression control of an essential BM component as a novel function for the tumor suppressor Smad4., shRNA interference suppresses endogenous Smad4 gene expression and subsequently modulates cell growth and apoptosis., aberration of the Transforming Growth factor-beta pathway, as indicated by a reduction or absence of Smad4 expression, promotes carcinogenesis of oral squamous cell carcinoma, identified a total of 47 protein species with a Smad4-dependent expression, mRNA expressed in human granulosa-luteal cells at oocyte retrieval., Cooperates with lymphoid enhancer-binding factor 1 to activate c-myc expression., DPC4 regulates MMP9 and may inhibit the proliferation of colon cancer cell by restraining growth and inducing apoptosis, Loss of SMAD4 expression was significantly more frequent in poorly differentiated carcinoma and signet-ring cell carcinoma of the colorectum, SMAD4 loss in gastric carcinomas is due to several mechanisms, including LOH, hypermethylation, and proteasome degradation, Smad4 mediates down-regulation of E-cadherin induced by TGF-beta in PANC-1 cells, at least in part, through Snail and Slug induction., Transgenic Smad4 has a role in the maintenance of hematopoietic stem cell self-renewal and reconstituting capacity., Our results indicate that absence of Smad4 expression correlated significantly with liver metastases regardless of the time of their occurrence and represents a promising new biomarker to predict liver metastasis in colorectal cancer patients., Mutations of K-ras and Dpc4 genes can accumulate already in non-malignant, inflammatory pancreatic tissue, suggesting its applicability in monitoring of further destruction of pancreatic tissue and progression into malignancy., Correlation of the expression of S100A8 and S100A9 revealed that the microenvironments of tumours which lacked expression of Smad4, had significantly reduced numbers of S100A8-immunoreactive (p = 0.023) but not S100A9-immunoreactive (p = 0.21) cells., examined the possible deterioration in the pathway in human squamous cancer cell lines, focusing on intracellular localization of S100C/A11 and its functional partners Smad3 and Smad4, Proinvasive activity of BMP7 through SMAD4/src-independent and ERK/Rac/JNK-dependent signaling pathways in colon cancer cells is reported., Results show that Arkadia specifically activates transcription via Smad3/Smad4 binding sites by inducing degradation of the transcriptional repressor SnoN., Smad4 siRNA treatment completely abolished TGFb-induced early gene upregulation, indicating the absence of the rapid activation of Smad signaling., combined with screening of K-ras mutations and allelic losses of tumor suppressors p16 and DPC4 represents a very sensitive approach in screening for pancreatic malignancy., study suggests that SMAD4 is an important marker for confirming a diagnosis of pancreatic adenocarcinoma as a primary tumor, as well as when it presents as a metastatic tumor on small fine-needle aspirate samples, 5 nonsense, 6 frameshift and 4 missense mutations (2 new) were associated with juvenile polyposis syndrome., Mutant p53 attenuates TGF-beta1 signaling. This was exhibited by a reduction in SMAD2/3 phosphorylation and an inhibition of both the formation of SMAD2/SMAD4 complexes and the translocation of SMAD4 to the cell nucleus., functional characterization of a tumorigenic mutation in Smad4(E330A); findings show this mutant & a Smad3 mutant (Smad3 E239A) failed to activate transcription in response to TGFbeta stimulation because of defects in oligomerization, Smad4 has a role in extracellular matrix composition in cervical cancer, Large genomic deletions of SMAD4, BMPR1A and PTEN are a common cause of JPS., We failed to find evidence of genomic deletions or amplifications affecting the Smad4 locus on chromosome 18 in advanced prostate cancer., loss of Smad4 contributes to aberrant RON expression and cross-talk of Smad4-independent TGF-beta signaling and the RON pathway promotes an invasive phenotype, vidence for a cross talk between Smad4 and the Wnt/beta-catenin pathway in pancreatic carcinoma cells., Data show that the expression of key transcription factors, phosphorylated Smad1 protein, and the nuclear accumulation of Smad1 and Smad4 are inhibited by Ubc9 silencing., Smad4 is a target molecule for functional inactivation in cervical cancer., In MSI CRC this is associated predominantly with impaired BMPR2 expression and in MSS CRC with impaired SMAD4 expression., 18505344:DPC$ might be involved in preventing the tumor metastasis by inhibiting tumor angiogenesis., TGF-beta-induced and basal state spontaneous nuclear import of Smad4 require importin 7 and 8., loss of Smad4, leading to aberrant activation of STAT3, contributes to the switch of TGFbeta from a tumor-suppressive to a tumor-promoting pathway in pancreatic cancer, Data demonstrate that in response to TGFbeta stimulation the transcriptional regulator TAZ binds heteromeric Smad2/3-4 complexes and is recruited to TGFbeta response elements., Deleted in pancreatic carcinoma locus 4 might be an important biomarker for malignant transformation and be involved in inducing apoptosis by modulating Bcl-2/Bax balance., Smad4 mediates transcriptional regulation through three mechanisms, The overall prevalence of SMAD4 and BMPR1A point mutations and deletions in JPS was 45% in the largest series of patients to date, TGF-beta1-induced cell growth inhibition by up-regulating p16 expression and cellular apoptosis by activating caspase 3 was Smad4-dependent, Inhibition of pancreatic carcinoma cell growth in vitro by DPC4 gene transfection., The inactivation of SMAD4 is similar in familial pancreatic adenocarcinomas as in sporadic pancreatic adenocarcinomas., The association between v-ErbA and Smad4 is essential for the dysregulation of TGF-beta signaling., There was no association between SMAD4(MAD homolog 4) protein expression, SMAD4 copy number, family history, Microsatellite instability status, tumour stage or grade in patients with early onset colorectal cancer, Both solitary and SMAD4 mutated JP case showed extensive co-localization of the alterations described above, The majority of the cases of Adenosquamous carcinoma of the pancreas had loss of Dpc4 protein, mutational analysis of the SMAD4 gene in Korean patients with hereditary hemorrhagic telangiectasia., The data suggested that restoration of Smad4 in Smad4-deficient cells may provide a potential therapeutic strategy for intervention of colon cancer migration and metastasis., Smad4 is dispensable for enhanced invasiveness of human colorectal cancer cells due to BMP-4 overexpression., Results suggest a mechanism by which a balance between Smad4 and Smad7 in human gastric cancer is critical for differentiation, metastasis, and apoptosis of tumor cells., The prevalence of germline mutations of BMPR1A and SMAD4 are about 20% each in the patient with JPS., Low expression of Smad4 and TbetaRII may promote metastasis of oral squamous cell carcinoma., Study shows that Sp1 alone or the combination of Smad2 and Smad4 activated the alpha(1)(I) collagen promoter in transfected LX-2 stellate cells., Data show that SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically resected adenocarcinoma of the pancreas., Smad4 expression was related with tumor differentiation and Lauren classification of gastric cancer., Strong Smad4 expression is associated with hepatocellular carcinoma., Smad4 was found in the regions relatively distant from the transcription start sites, while Smad2/3 binding regions were more often present near the transcription start sites., Study data demonstrates downregulated SMAD4 expression in psoriatic skin., threonine 9 (Thr9) and Serine 138 (Ser138) within the N-terminal Mad homology1 (MH1) domain of Smad4 could be phosphorylated by NLK, Linoleic acid induces PAI-1 expression in breast cancer cells through SMAD4., 4E-BP1 gene appears critical for TGFbeta/Smad4-mediated inhibition of cell proliferation., connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation, a predictive marker of pancreatic ductal adenocarcinoma cell permissiveness for oncolytic infection with parvovirus H-1PV, Mutations and/or alterations in expression of TGF-beta receptors and loss of Smad 4 are frequent in human ovarian cancers., BMP9 acts as a proliferative factor for immortalized ovarian surface epithelial cells and ovarian cancer cell lines, signaling predominantly through an ALK2/Smad1/Smad4 pathway, the major BMP9 receptor in endothelial cells., Expression of TGF-beta1 and its downstream effectors Smad4 and Smad7 was assessed & only Smad4 was found to have possible predictive value for esophageal squamous cell carcinoma in patients receiving neoadjuvant chemoradiotherapy., analysis of SMAD4 mutations with juvenile polyposis (JP) and JP-HHT syndrome, The ectopic expression of miR-224 can enhance TGF-beta1-induced GC proliferation through targeting Smad4., The expression of TGF-beta1, its receptor TGFbetaRII, and signaling proteins Smad4 and Smad7 was observed in the majority of colorectal cancer specimens., SMAD4 is not required for maintenance of the undifferentiated state of human embryonic stem cells, but rather to stabilize that state., BMP2 is both negatively and positively regulated by Smad4 and YY1 bound to a promoter region in cerebral cortex neurons., Smad4-reconstituted colon carcinoma cells respond to TNFalpha by increased laminin-332 expression; coincubation with TGFbeta and TNFalpha leads to synergistic induction and to the secretion of large amounts of the heterotrimer., We assessed the immunohistochemical expression profiles of Smad2, P-Smad2, Smad4, and p21/WAF1 proteins in 34 cases of osteosarcoma, SMAD4 regulates inositol-1,4,5-trisphosphate 5-phosphatase (SHIP1) and interleukin-1 receptor-associated kinase 3 (IRAK-M) expression during lipopolysaccharide-induced development of endotoxin tolerance., Our study indicates for the first time, that oncogenic ras and loss of Smad signaling cooperate to upregulate EGFR and erbB2, which plays a role in promoting invasion., Observed a significant association of SMAD4 gene aberrations with KRAS mutant status suggesting the involvement of at least two molecules in the advanced tumor grade in colorectal cancers in a Kashmiri population., RETINOIC ACID UPREGULATES MIR146A AND DOWNREGULATES SMAD4 IN APL CELLS, Study identified driver mutations in three known pancreatic cancer driver genes P53, SMAD4 and CDKN2A., Smad4 loss alters the tumor's interaction with stromal myeloid cells and the tumor cells' response to the stromal chemokine, S100A8., different routes to neoplasia in Juvenile polyposis syndrome caused by germline SMAD4 mutation seem to be operative, Results provide further evidence for a role of SMAD4 as a regulator of invasion, a process of prime importance in carcinogenesis but hitherto poorly understood in molecular terms., Reduction of SMAD4 may play a significant role in thyroid carcinogenesis., cooperative regulation of estrogen signaling by FHL2 and Smad4 in breast cancer cells, and might provide a new regulation mechanism underlying breast cancer development and progression, Smad4 suppresses human ovarian cancer cell metastasis potential through its effect on the expressions of PAI-1, E-cadherin and VEGF., New Smad4 dependent and independent TGF-beta responses in colon carcinoma cells, were identified., TGFbeta1 down-regulated expression of prolactin and IGFBP-1 in endometrial stromal cells in SMAD4-dependent and SMAD4-independent manners., SMAD4 gene promoter haplotype -462T(14)/-4T(10) was found in 85% of pancreatic cancer tissues, but it was not present in colorectal cancer tissues, PARP-1 dissociates Smad complexes from DNA by ADP-ribosylating Smad3 and Smad4, which attenuates Smad-specific gene responses and TGF-beta-induced epithelial-mesenchymal transition., These results suggest that genetic variants in the SMAD4 gene play a protective role in gastric cancer in a Chinese population., Findings identify miR-483-3p as a potent regulator of DPC4/Smad4, which may provide a novel therapeutic strategy for the treatment of DPC4/Smad4-driven pancreatic cancer., Individuals with the SMAD4 (rs10502913) AA genotype had an increased risk of coal work's pneumoconiosis., Results define a molecular mechanism that explains how loss of the tumor suppressor Smad4 promotes colorectal cancer progression, the aim of this study was to investigate the prognosis and clinicopathologic roles of beta-catenin, Wnt1, Smad4, Hoxa9, and Bmi-1 in esophageal squamous cell carcinoma, Loss of Dpc4 expression provides the most useful immunohistochemical evidence for establishing the pancreaticobiliary tract as the most likely source of these metastatic mucinous carcinomas in the ovary., Data indicate that hypoxia represses hepcidin expression through inhibition of BMP/SMAD4 signaling., This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of prostate cancer progression in mice and humans., proposed two possible model structures of Hoxa9 and Smad4 complex., show that Gata4 and Smad4 cooperatively activated the Id2 promoter, that human GATA4 mutations abrogated this activity, and that Id2 deficiency in mice could cause atrioventricular septal defects, these findings identify miR-421 as a potent regulator of DPC4/Smad4 in pancreas cancer., Juvenile polyps with a SMAD4 germline mutation were predominantly type B, whereas type A was more common among juvenile polyps with a BMPR1A germline mutation., The predicted transcription factor binding site profiles for each of the four SMAD4 promoters shared few transcription factors in common, but were conserved across several species., report of an individual whose family history was positive for aortopathy, mitral valve dysfunction, and juvenile polyposis syndrome; mutation analysis of SMAD4 implicates this gene for these phenotypes in this family, Data suggest a regulatory circuitry involving Smad4 dependent up-regulation of KRT23 (directly or indirectly) which in turn modulates the interaction between KRT23 and 14-3-3epsilon leading to a cytoplasmic sequestration of 14-3-3epsilon., SMAD4 knockdown accelerated this re-silencing process, suggesting that normal TGF-beta signaling is essential for the maintenance of RunX1T1 expression, TIF1gamma binds to and represses the plasminogen activator inhibitor 1 promoter, demonstrating a direct role of TIF1gamma in TGF-beta-dependent gene expression, Data indicate that Cal27 cells stably transfected with Smad4 showed similar resveratrol effects as parental Cal27, suggegsting that a lack of resveratrol effect in Det562 cells was independent of Smad4 status in these cells., Data shows that Smad4(Dpc4) immunostaining correlated with the pattern of disease progression in pancreatic adenocarcinoma., Smad4 overexpression promotes apoptosis in tongue squamous carcinoma cells, and decreases TGF-beta1-mediated cell migration and metastasis., The present finding that NF1/Smad4 repressor complexes are formed through TGF-beta signaling pathways suggests a new, but much broader, role for these complexes in the initiation or maintenance of the growth-inhibited state., SMAD4 may play an inhibitive role during the development of glioma and may be a potential prognosis predictor of glioma., in breast cancer cases SMAD4 was significantly over-expressed, A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency in PAH, pulmonary arterial hypertension., Results show that BMP4-induced changes in OvCa cell morphology and motility are Smad-dependent with shRNA targeting Smads 1, 4, and 5., novel findings that high SMAD4 expression predicts a better prognosis suggests that SMAD4 immunohistochemistry could constitute a prognostic marker in combination with CIMP and MSI screening status, It was shown that miR-146a functions as a novel negative regulator to modulate myofibroblast transdifferentiation during TGF-beta1 induction by targeting SMAD4., SMAD4, occurring in 12% of colorectal adenocarcinomas, correlated with the presence of lymph node metastases., miR-146a can directly target SMAD4, and suggest that miR-146a may play a role in the development of gastric cancer by modulating cell proliferation and apoptosis., Smad4 may help to identify a subset of colorectal cancer patients with early recurrence after curative therapy., Data show two miR-130a binding sites were identified in the 3'-untranslated region of the Smad4 mRNA., Smad4 C324Y mutation plays an important role in thyroid carcinogenesis and can be considered as a new prognostic and therapeutic target for thyroid cancer, Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of beta-catenin., Smad4-expressed cancer tissues not only show the elevated expression of PAK1, but also support our hypothesis that Smad4 induces PUMA-mediated cell death through PAK1 suppression., We identified three distinct heterozygous missense SMAD4 mutations affecting the codon for Ile500 in 11 individuals with Myhre syndrome., Compared with conventional carcinomas, serrated adenocarcinomas showed significantly reduced SMAD4, The present report identified a previously unrecognized class of mutations in the SMAD4 gene with profound impact on development and growth., Genetic alterations in SMAD4 and K-ras in Serbian patients with endometrial carcinoma., Data suggest that TGF-beta, TGF-betaR1, TGF-betaR2, Smad4, pSmad2/3, and E-cadherin are closely related to tumor-node-metastasis (TNM) stage of colorectal cancer (CRC)., Smad4 copy-number variations are associated with squamous cell carcinoma in skin cancers., decreased protein expression of Smad4 correlated with increased expression of TGF-beta1 in esophageal squamous cell carcinoma, Disruption of the bone morphogenetic protein signaling pathway is the likely etiology of juvenile polyposis in patients with SMAD4 germline mutations., analysis of Smad4 loss in pancreatic cancer versus head-and-neck cancer [review], Patients with hereditary hemorrhagic telangiectasia and SMAD4 mutations are at significant risk of juvenile polyposis and colorectal cancer, Lymph node ratio <0.2 (p = 0.004), tumor free resection margins (p = 0.044) and Smad4 expression (p = 0.004) were the only independent prognostic variables in the multivariate analysis., Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy benefit., Data suggest that the formation of transient TIF1gamma-Smad2-Smad4 ternary complexes is the only one that can account for TGF-beta signaling., SMAD4 mutations affect Smad4 protein expression to different extents, depending on their location within the gene. SMAD4 gene alterations predict a worse outcome for patients with pancreatic ductal adenocarcinoma., Missense mutations of SMAD4 account for both LAPS and Myhre syndromes., This report describes a new SMAD4 mutation in a large family leading to considerable variations in juvenile polyposis syndrome manifestations in the individual patients., when the SNON-SMAD4 complex is absent as in some cancer cells lacking SMAD4 the regulation of some TGF-beta target genes is modified, TGF-beta signaling has a role in nuclear localization of transcription factor Smad4, study demonstrates that the overexpression of Tob1 inhibits gastric cancer progression by activating Smad4- and inhibiting betacatenin-mediated signaling pathways, A 4-bp deletion in exon 9 of SMAD4 gene was found in a family with juvenile polyposis syndrome, where one member exhibited a particular form of hyperplastic gastropathy diagnosed as Menetrier's disease with Helicobacter pylori infection., This study identified a group of miRNAs predicted to target Smad4, of which miR-199a was demonstrated to directly target Smad4 and modulate the response to TGF-beta signalling in cell lines and gastric cancer., results indicated that the low-expression levels of RhoT1 and Smad4 were significantly associated with LNM and shorter survival. RhoT1 may be considered as a potential novel marker for predicting the outcome in patients with pancreatic cancer, We show that the downregulation of AGR2 in human pancreatic cancer cells is SMAD4 dependent., a SMAD4-dependent pathway plays a role in regulating mRNA entry into polysomes, Smad signaling circuitry negatively regulates the regeneration capacity of human hematopoietic stem/progenitor cells in vivo., specific down regulating of p53 can significantly increase the expression of Smad4 in cancer cell line MCF7 and promote cell apoptosis., The upregulation of Smad4 in HepG2 cells followed inhibition of cell proliferation by nimesulide., The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively., The effects of transgenic Tif1gamma knockdown on lactation depend on both SMAD4 and transforming growth factor (TGF)beta; Tif1gamma expression pattern in mammary epithelial cells is almost symmetrically opposite to that described for TGFbeta., The results suggest a possible link between downregulation of LKB1 and overexpression of SMAD4 in SGTs., miR-204-5p overexpression enhanced the repression of TGF-beta2-induced EMT in the presence of SMAD4 small interfering RNA., miR-182-5p plays an important role as an oncogene by knocking down RECK and Smad4, resulting in activation of the Wnt-beta-catenin signaling pathway in bladder cancer., We found two patients with juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia and thoracic aortic enlargement associated with SMAD4 mutations, Results indicate that the crosstalk between IL-6 and TGF-beta1 is associated with malignant features, including epithelial-mesenchymal transition (EMT), and Smad4 works in a dominant manner to promote these features., Report DPC4 mutations in pancreatic ductal carcinoma and their relationship to patient survival., Primary tumor SMAD4 expression status was not a predictor of recurrence pattern in a large cohort of patients with resected pancreatic ductal adenocarcinoma., Smad4 and the R subunit of the protein kinase A holoenzyme form a functional complex in vivo in response to TGFbeta., Seventy-seven patients (13%) were found to have colorectal polyposis-associated mutations, including 21 in SMAD4 (3.5%)., Expression of CDKN2A/p16, TP53, and SMAD4/DPC4 strongly predicts survival in patients with resectable pancreatic ductal adenocarcinoma., Data identifies Dkk-3 and SMAD4 as potential target genes of miR-183 in prostate cancer., The stable expression of Smad4 protein with C324Y mutation in thyroid cells is responsible of TSH independent cell growth ability., SMAD4 is crucial for granulosa cells terminal differentiation during ovulation., Nuclear expressions of Smad3 and Smad4 were related to prognosis of clear cell renal cell carcinoma patients and may serve as novel prognostic markers in clear cell renal cell carcinoma patients., Smad4 is directly downregulated by miR-205. Smad 4 mRNA levels are not affected but Smad4 protein is decreased by miR-205 overexpression and increased by miR-205 inhibition., Increased SMAD4 expression is associated with chemoresistance in breast cancer., The combination of SMAD4 expression and histological grade of dysplasia is a better predictor for the malignant transformation of oral leukoplakia., Data show that Smad4 might be a target of miR-146a to exert miR-146a functions during photoaging., Down-regulation of L1ORF1p suppresses tumorigenesis in vitro and in vivo. L1ORF1p is responsible for Smad4 sequestration in the cytoplasm., In human colorectal cancer cells, loss of SMAD4 leads to up-regulation of CCL15 expression., miR-224/SMAD4 pathway is a clinically relevant pathway to provide new insights in understanding hepatocellular cancer., One SNP in the SMAD4 gene having association with chronic otitis media with effusion in study population., data show SMAD4 expression in breast cancer is lower than in normal adjacent breast epithelial tissue and that SMAD4 expression levels were inversely related to histologic grade; data provide evidence that the reduced expression of SMAD4 may play an important role during the development of ductal breast carcinoma, The expression of Smad4 was associated with the histological grade, clinical stage, and metastasis of ICC (P < 0.05)., Stem cells with Kras(G12D) activation and Smad4 depletion can produce tumors that are multipotent and susceptible to epithelial mesenchymal transformation and metastasis., Smad2 and PIAS1 proteins were significantly upregulated resulting in dramatically increased interactions between Smad2/4 and PIAS1 in the presence of zinc., Smad4 was intact in 15 (52%) and lost in 14 (48%) specimens. Overall survival was 24.4 months versus 18.3 months in patients with intact Smad4 status versus those with loss of Smad4, miR483-3p and Smad4 expression may help in distinguishing adrenal cortical carcinomas and adenomas., Clathrin and caveolin-1 have a role in docking of SMAD4 at the cell membrane., GATA3 abrogated the canonical TGFbeta-Smad signaling by abolishing interactions between Smad4 and its DNA binding elements, Valproic acid could suppress invasiveness of prostate cancer cell lines PC3 and Du145, possibly through multiple pathways other than the SAMD4 pathway., alphaB-crystallin is over-expressed in fibrotic lung tissue and favors TGF-beta1 pathway via its role in modulating the cellular localization of Smad4., We report a novel germline mutation in exon 10 of the SMAD4 gene in familial juvenile polyposis patients., ZNF451 acts as a transcriptional corepressor for Smad3/4 and negatively regulates TGF-beta signaling., Oncogenic K-Ras and loss of Smad4 mediate invasion by activating an EGFR/NF-kappaB Axis that induces expression of MMP9 and uPA in human pancreas progenitor cells., Smad4 represents a barrier in KRAS-mediated malignant transformation of the near normal immortalized human pancreatic duct epithelial (HPDE) cell, Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome., Data suggest genistein exerts its anti-tumour effect via downregulation of miR-1260b that targeted sRRP1 and Smad4 genes in prostate cancer cells. Expression of sFRP1 and Smad4 was modulated via DNA methylation or histone modifications in PC., This multicenter retrospective chart review of 34 individuals with SMAD4 mutations associated with juvenile polyposis syndrome- and hereditary hemorrhagic telangiectasia (JP-HHT) provides additional documentation of the clinical phenotypic spectrum associated with these mutations., SMAD4 is the gene responsible for Myhre syndrome., data suggest that PGE2 had no effects on Smad2 phosphorylation, suggesting that PGE2-mediated Smad2-Smad4 complex formation is independent of TGF-beta signaling, loss of SMAD4 immunohistochemical expression is associated with loss of heterozygosity at chromosome 18q and is always associated with aggressive histologic features in disseminated appendiceal mucinous neoplasms, acetaldehyde up-regulates COL1A2 by modulating the role of Ski and the expression of SMADs 3, 4, and 7., Our results revealed that the loss of Smad4 expression correlated significantly with the intestinal type, male sex, depth of tumor and poor survival, Preoperative SMAD4 staining showed a strong correlation with postoperative staining and predicted metastases in locally advanced pancreatic ductal adenocarcinoma., Loss of SMAD4 alters BMP signaling to promote colorectal cancer cell metastasis via activation of Rho and ROCK., Analysis of the mechanism regulating this interplay identified a new transcriptional complex including GLI1 and the TGFbeta-regulated transcription factor, SMAD4., Loss of SMAD4 in PDAC cells leads to reduced levels of miR-494, increased levels of FOXM1, and nuclear localization of beta-catenin in pancreatic ductal adenocarcinoma., Our results indicated that KGN promoted the type-I collagen synthesis of dermal fibroblasts in vitro and in the dermis of mice through activation of the smad4/smad5 pathway., High SMAD4 expression is associated with recurrence after resection of colorectal liver metastases., Results indicate that the tumor-suppressive function of SMAD4 is mediated by downregulation of b-catenin transcriptional activity via AURKA degradation in a TGFb-independent manner., Activin A, B, and AB produce comparable increases in human trophoblast cell invasion by up-regulating N-cadherin expression in a SMAD2/3-SMAD4-dependent manner., microRNA 376c (miR-376c) significantly enhanced neural differentiation of hPSCs in a defined condition by suppressing SMAD4, Ductal adenocarcinoma of the pancreas metastasing to the liver retained the primary tumour's SMAD4/TP53 protein status., The expression levels of collagens type I/III, TGF-beta1, Smad2/3/4/7 and PAI-1 (plasminogen activator inhibitor type 1) in gluteal muscle contraction (GMC) patients were measured., TGF-beta-mediated suppression of ANT2 through NF1/Smad4 complexes contributes to oxidative stress and DNA damage during induction of cellular senescence., Nodal signaling pathway has subtle changes in the endometrium of women with endometriosis, but this imbalance may not cause functional damage as it seems not to affect the nuclear expression of SMAD4., findings suggest that SMAD4 is critical for the TGF-beta-driven upregulation of N-cadherin and the resultant invasive phenotype of human pancreatic ductal epithelial cells during EMT, Smad4 expression had prognostic significance in esophageal squamous cell carcinoma., loss of Smad4 staining could act as an unfavorable biomarker in the prognosis of various cancers and should be used as a powerful tool in future clinical trials., Smad3/4 is a novel drug sensitivity regulator in TGFbeta-mediated chemotherapy-resistant colorectal cancer cells., The results show that germline mutation in the SMAD4 is associated with a more aggressive upper gastrointestinal malignancy risk in juvenile polyposis syndrome, The BMP signalling pathway differentially modulates Wnt signalling dependent on the SMAD4 and p53 status., Groove pancreatic ductal adenocarcinomas are well differentiated and have intact Smad4 expression., SMAD4 funtion in progression and prognosis of pancreatic cancer. [Review], These results indicate that Smad4 acts as a tumor suppressor by activating FOXH1, and then suppressing the expression of estrogen receptor, in addition to tumor migration and invasion., Taken together, all these data suggest that Pokemon is a new partner of Smad4 and plays a negative role in TGF-beta pathway., NEK6 suppresses the cell growth arrest induced by TGFbeta. Mechanically, NEK6 blocks nuclear translocation of Smad4, which is essential for TGFbeta function., drastic elevation of nuclear SMAD4 in sub-population of HCC tumors highlights its potential as an outcome predictor for patient stratification and a target for personalized therapeutic development, DRAK1 was predominantly localized in the cytoplasm and bound to Smad3, thereby interrupting Smad3/Smad4 complex formation, which is the core process for the induction of tumor suppressor genes by TGF-beta1, Loss of Smad4 protein expression correlates with increased propensity for disease recurrence and poor survival in patients with esophageal adenocarcinoma after surgical resection., plays an important role in glioma development by regulating cell proliferation, Loss of Smad4 expression is associated with worse disease-free and overall survival in multiple subsets of patients with colorectal cancer., Downregulation of Smad4 enhances and increases sensitivity of colon carcinoma HCT116 cells to doxorubicin., PIK3CA, SMAD4, and TP53 are most often involved in clonal divergence, providing potential targets that may help guide the clinical management of tumor progression or metastases., This study has shown that functionally relevant somatic alterations of the SMAD4 gene promoter are found in some colon cancer tumors., The loss of SMAD4 expression is an independent prognostic factor in pancreatic cancer and seems to be associated with tumor progression, pattern of failure, and epithelial-to-mesenchymal transition status., the present study provides the first evidence that SMAD4 deletion is involved in pancreatic cancer initiating cell maintenance, Loss of Smad4 expression is associated with lymph node metastasis in lung adenocarcinoma, Studies establish Smad4 as a lung tumor suppressor and suggest that the defective DNA repair phenotype of Smad4-deficient tumors can be exploited by specific therapeutic strategies., Induction of neural crest genes by beta-catenin is repressed by SMAD2/SMAD3, ensuring proper lineage specification., Routine aortic imaging, including measurements of the aorta, should be considered in patients with SMAD4 mutations to allow for appropriate medical and surgical recommendations, MiR-301a-3p functions as a novel oncogene in pancreatic ductal adenocarcinoma and the oncogenic activity may involve its inhibition of the target gene SMAD4, Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma., Studied miR-34a expression levels in extrahepatic cholangiocarcinoma; found Smad4 over-expressed in most EHCC patients; activation of miR-34a suppressed invasion and migration through TGF-beta/Smad4 signaling pathway., This study has detected three novel SMAD4 promoter variants in patients with thyroid tumors. They all affect predicted binding sites of transcription factors involved in cell cycle regulation and should be further characterized functionally., germline SMAD4 gene mutation is associated with gastric polyposis., The SMAD4 processed pseudogene affects next-generation sequencing results by confounding the alignment of the sequences, resulting in erroneous variant calls. We recommend Sanger sequencing confirmation for SMAD4 variants., SMAD4 protein expression, however, was lost in 8 (57%) of 14 juvenile polyps with 6 showing concomitant loss in both, the epithelial and stromal, compartments., Positive COUP-TF II expression levels has significant value in determining CRC stage and metastasis and cooperates with negative Smad4 expression contributing to assess prognosis in patients with colorectal cancer., Microarray analysis of gene expression at 8, 24, and 48 hours after SMAD4 expression characterized the regulatory impact of SMAD4 expression in a SMAD4-null pancreatic ductal adenocarcinoma cell line and identified novel targets of TGF-beta signaling., Overexpression of the BMP4/SMAD4/SMAD5 signaling pathway could predict poor clinical outcome in skull base chordomas, suggesting activation of this pathway is involved in chordoma pathogenesis., Relationship between Expression of TGF-beta1, Smad2, Smad4 and Prognosis of Patients with Resected Non-small Cell Lung Cancer, The reverse correlation of Jab1 and Smad4 in PANC-1 cells may be involved in the Pathogenesis of prostate cancer. Jab1 can cause degradation of Smad4 via TGF-beta signal pathway., Transcription factor SMAD4 (a part of the TGF-beta signaling pathway) activates Fn14 expression. Then, activated Fn14 expression increases extracellular matrix synthesis and fibroblast activation., Smad4-dependent TGF-beta signaling in smooth muscle cells protects against aortic aneurysm formation and dissection., MicroRNA-483-3p has an inhibitory effect on ECM production in HTMCs through downregulating Smad4, which indicates that miR-483-3p may serve as a potential therapeutic target in glaucoma., In operated pancreatic adenocarcinoma, incidence of mutations was, data suggest that TGF-beta1 enhances IGFBP7 via Smad2/4 pathways, and that IGFBP7 might be involved in the TGF-beta1-induced tubular injury in DN., structure of DNA-binding domain,
OMIM_DISEASE Myhre syndrome, Polyposis, juvenile intestinal, Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Pancreatic cancer, somatic,
SP_COMMENT disease:Defects in SMAD4 are a cause of juvenile polyposis syndrome (JPS) [MIM:174900]; also known as juvenile intestinal polyposis (JIP). JPS is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers., disease:Defects in SMAD4 are a cause of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:175050]. JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic aetiology of this association is unknown., disease:Defects in SMAD4 are a cause of pancreatic carcinoma [MIM:260350]., disease:Defects in SMAD4 may be a cause of colorectal cancer (CRC) [MIM:114500]., function:Common mediator of signal transduction by TGF-beta (transforming growth factor) superfamily; SMAD4 is the common SMAD (co-SMAD). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. May act as a tumor suppressor., PTM:Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade., similarity:Belongs to the dwarfin/SMAD family., similarity:Contains 1 MH1 (MAD homology 1) domain., similarity:Contains 1 MH2 (MAD homology 2) domain., subcellular location:Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R-SMAD., subunit:May form trimers with receptor-regulated SMAD (R-SMAD). Found in a ternary complex composed of SMAD4, STK11 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11, STK11IP and TRIM33. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with USP9X.,