Gene Symbol: Smad4
Description: SMAD family member 4
Alias: Madh4, mothers against decapentaplegic homolog 4, MAD (mothers against decapentaplegic Drosophila) homolog 4, MAD homolog 4, SMAD 4, mothers against DPP homolog 4
Species: rat
Products:     Smad4

Top Publications

  1. Zhang Y, Feng X, We R, Derynck R. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature. 1996;383:168-72 pubmed
    ..These results define hMAD-3 and -4 as effectors of the TGF-beta response and demonstrate a function for DPCA-4/hMAD-4 as a tumour suppressor. ..
  2. Simeone D, Zhang L, Graziano K, Nicke B, Pham T, Schaefer C, et al. Smad4 mediates activation of mitogen-activated protein kinases by TGF-beta in pancreatic acinar cells. Am J Physiol Cell Physiol. 2001;281:C311-9 pubmed
    ..Furthermore, adenoviral-mediated expression of dominant negative Smad4 blocked the ability of TGF-beta to activate acinar cell MAP kinase, demonstrating that this activation is ..
  3. Lin E, Kong L, Bai X, Luan Y, Liu C. miR-199a, a bone morphogenic protein 2-responsive MicroRNA, regulates chondrogenesis via direct targeting to Smad1. J Biol Chem. 2009;284:11326-35 pubmed publisher
    ..Mechanism studies revealed that miR-199a(*) inhibits Smad1/Smad4-mediated transactivation of target genes, and that overexpression of Smad1 completely corrects miR-199a(*)-..
  4. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685-700 pubmed
    ..This article reviews these latest advances and presents our current understanding on the mechanisms of TGF-beta signaling from cell membrane to the nucleus. ..
  5. Cardillo M, Lazzereschi D, Gandini O, Di Silverio F, Colletta G. Transforming growth factor-beta pathway in human renal cell carcinoma and surrounding normal-appearing renal parenchyma. Anal Quant Cytol Histol. 2001;23:109-17 pubmed
    ..Our data support the concept that the reduction of T beta RII and SMAD proteins in renal cell carcinomas is involved in tumor development and suggest an altered TGF-beta/SMAD signaling pathway in kidney neoplasia. ..
  6. Izzi L, Silvestri C, Von Both I, Labbé E, Zakin L, Wrana J, et al. Foxh1 recruits Gsc to negatively regulate Mixl1 expression during early mouse development. EMBO J. 2007;26:3132-43 pubmed
    ..As Gsc is itself induced in a Foxh1-dependent manner, we propose that Foxh1 initiates positive and negative transcriptional circuits to refine cell fate decisions during gastrulation. ..
  7. Akool E, Doller A, Babelova A, Tsalastra W, Moreth K, Schaefer L, et al. Molecular mechanisms of TGF beta receptor-triggered signaling cascades rapidly induced by the calcineurin inhibitors cyclosporin A and FK506. J Immunol. 2008;181:2831-45 pubmed
  8. Fritzmann J, Morkel M, Besser D, Budczies J, Kosel F, Brembeck F, et al. A colorectal cancer expression profile that includes transforming growth factor beta inhibitor BAMBI predicts metastatic potential. Gastroenterology. 2009;137:165-75 pubmed publisher
    ..The metastatic expression signature we describe, along with BAMBI levels, can be used in prognosis. Developmental signaling pathways appear to act in hierarchies and cooperate in tumor cell migration, invasion, and metastasis. ..
  9. Hao J, Wang B, Jones S, Jassal D, Dixon I. Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro. Am J Physiol Heart Circ Physiol. 2000;279:H3020-30 pubmed day(-1)) normalized total Smad 2 overexpression in infarct scar and remnant heart tissue and normalized Smad 4 in infarct scar. Phosphorylated Smad 2 (P-Smad 2) staining decreased in cytosol from failing heart vs...

More Information


  1. Liu L, Santora R, Rao J, Guo X, Zou T, Zhang H, et al. Activation of TGF-beta-Smad signaling pathway following polyamine depletion in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2003;285:G1056-67 pubmed
    ..Depletion of cellular polyamines by alpha-difluoromethylornithine (DFMO) increased basal levels of Smad3 and Smad4 proteins, induced their nuclear translocation, and stimulated Smad sequence-specific DNA-binding activity...
  2. Yoon S, Wills A, Chuong E, Gupta R, Baker J. HEB and E2A function as SMAD/FOXH1 cofactors. Genes Dev. 2011;25:1654-61 pubmed publisher
    ..Taken together, E proteins are novel Nodal signaling cofactors that associate with SMAD2/3 and FOXH1 and are necessary for mesendoderm differentiation. ..
  3. Ramos M, Lame M, Segall H, Wilson D. Smad signaling in the rat model of monocrotaline pulmonary hypertension. Toxicol Pathol. 2008;36:311-20 pubmed publisher
    ..b>Smad 4 was localized by immunohistochemistry to endothelial nuclei of the intra-acinar vessels undergoing remodeling...
  4. Yang L, Cai C, Lin L, Qyang Y, Chung C, Monteiro R, et al. Isl1Cre reveals a common Bmp pathway in heart and limb development. Development. 2006;133:1575-85 pubmed
    ..Tbx3 is required for heart and limb formation, and is mutated in ulnar-mammary syndrome. We provide evidence that the Tbx3 promoter is directly regulated by Bmp Smads in vivo. ..
  5. Sun Y, Fei T, Yang T, Zhang F, Chen Y, Li H, et al. The suppression of CRMP2 expression by bone morphogenetic protein (BMP)-SMAD gradient signaling controls multiple stages of neuronal development. J Biol Chem. 2010;285:39039-50 pubmed publisher
    ..Thus, our study reveals a novel mechanism that the BMP-SMAD signaling pathway controls neuronal migration and neurite outgrowth by suppressing the transcription of CRMP2. ..
  6. Nawshad A, Hay E. TGFbeta3 signaling activates transcription of the LEF1 gene to induce epithelial mesenchymal transformation during mouse palate development. J Cell Biol. 2003;163:1291-301 pubmed
    ..out other TGFbeta3 targets, such as RhoA and MEK1/2 pathways, and we present evidence using dominant-negative Smad4 and dominant-negative LEF1 showing that TGFbeta3 uses Smads both to up-regulate synthesis of LEF1 and to activate ..
  7. Li J, Huang J, Dai L, Yu D, Chen Q, Zhang X, et al. miR-146a, an IL-1? responsive miRNA, induces vascular endothelial growth factor and chondrocyte apoptosis by targeting Smad4. Arthritis Res Ther. 2012;14:R75 pubmed publisher
    ..Primary chondrocytes from Sprague-Dawley rats were treated with IL-1? before the expression levels of miR-146a, Smad4 and vascular endothelial growth factor (VEGF) were quantified by real-time PCR and/or western blotting...
  8. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang R, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood. 2008;112:1503-9 pubmed publisher
    ..consequence similar changes in Smad1/5/8 phosphorylation that leads to formation of heteromeric complexes with Smad4 and their translocation to the nucleus...
  9. Zhang P, Hou S, Chen J, Zhang J, Lin F, Ju R, et al. Smad4 Deficiency in Smooth Muscle Cells Initiates the Formation of Aortic Aneurysm. Circ Res. 2016;118:388-99 pubmed publisher
    ..b>Smad4 is the central mediator of the canonical TGF-β signaling pathway...
  10. Dong M, Jia Y, Zhang Y, Li C, Geng Y, Zhou L, et al. Emodin protects rat liver from CCl(4)-induced fibrogenesis via inhibition of hepatic stellate cells activation. World J Gastroenterol. 2009;15:4753-62 pubmed
    ..The mRNA levels of transforming growth factor-beta1 (TGF-beta1), Smad4 and alpha-SMA in liver tissues were significantly down-regulated in SD rats that received emodin treatment...
  11. Chu G, Dunn N, Anderson D, Oxburgh L, Robertson E. Differential requirements for Smad4 in TGFbeta-dependent patterning of the early mouse embryo. Development. 2004;131:3501-12 pubmed
    Genetic and biochemical data have identified Smad4 as a key intracellular effector of the transforming growth factor beta (TGFbeta superfamily of secreted ligands...
  12. Wang E, Ma E, Woodruff T. Activin signal transduction in the fetal rat adrenal gland and in human H295R cells. J Endocrinol. 2003;178:137-48 pubmed
    ..Notably, the presence of Smad4 protein is significantly increased after birth in the rat adrenal gland...
  13. Thuault S, Tan E, Peinado H, Cano A, Heldin C, Moustakas A. HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem. 2008;283:33437-46 pubmed publisher
    ..The data propose that HMGA2 acts in a gene-specific manner to orchestrate the transcriptional network necessary for the EMT program. ..
  14. Zeng L, Rowland R, Lele S, Kyprianou N. Apoptosis incidence and protein expression of p53, TGF-beta receptor II, p27Kip1, and Smad4 in benign, premalignant, and malignant human prostate. Hum Pathol. 2004;35:290-7 pubmed
    ..transforming growth factor (TGF)-beta receptor II (TbetaRII), a critical signaling effector of TGF-beta; Smad4, a downstream intracellular effector of TGF-beta signaling; p53, a key apoptosis regulator; and prostate-specific ..
  15. Luo B, Niu R, Feng J, Hu C, Xie X, Ma L. Downregulation of secretory leukocyte proteinase inhibitor in chronic obstructive lung disease: the role of TGF-beta/Smads signaling pathways. Arch Med Res. 2008;39:388-96 pubmed publisher
    ..Spirometry was conducted, and expressions of TGFbeta(1), Smad4 and SLPI were examined by immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR), ..
  16. Wang Y, Lu S, Zhao Z, Zhao Y, Wang N, Jing D, et al. [Expressions of transforming growth factor-beta(1) and Smad4 in rat models of chronic nonbacterial prostatitis and their clinical significance]. Zhonghua Nan Ke Xue. 2010;16:490-4 pubmed
    To investigate the expressions of transforming growth factor-beta(1) and Smad4 in the prostatic tissue of rat models of chronic nonbacterial prostatitis (CNP), and to explore the mechanisms of CNP and its fibrosis...
  17. Takakura S, Okamoto A, Saito M, Yasuhara T, Shinozaki H, Isonishi S, et al. Allelic imbalance in chromosome band 18q21 and SMAD4 mutations in ovarian cancers. Genes Chromosomes Cancer. 1999;24:264-71 pubmed
    Recently, three candidate tumor suppressor genes, SMAD2 (MADR2/JV18-1), SMAD4 (DPC4), and DCC, were identified in chromosome band 18q21...
  18. Zhang M, Wang M, Tan X, Li T, Zhang Y, Chen D. Smad3 prevents beta-catenin degradation and facilitates beta-catenin nuclear translocation in chondrocytes. J Biol Chem. 2010;285:8703-10 pubmed publisher
    ..Both Smad3 and Smad4 were required for the interaction with beta-catenin and protected beta-catenin from an ubiquitin-proteasome-..
  19. Zhou X, Huang W, Xu Y, Yang M. [High glucose induces sumoylation of Smad4 via SUMO2/3 in glomerular mesangial cells]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2014;45:380-5 pubmed
    To investigate the expression of SUMO2/3 and Smad4 in rat glomerular mesangial cells (GMCs) induced by high glucose, and the interaction between small ubiquitin related modifier (SUMO)2/3 and Smad4; and to explore the role and mechanism ..
  20. Raychaudhuri S. MicroRNAs overexpressed in growth-restricted rat skeletal muscles regulate the glucose transport in cell culture targeting central TGF-β factor SMAD4. PLoS ONE. 2012;7:e34596 pubmed publisher
    ..We have identified through a series of experiments one important protein factor SMAD4, a co-SMAD critical to the TGF-beta signaling pathway...
  21. He Y, Huang C, Sun X, Long X, Lv X, Li J. MicroRNA-146a modulates TGF-beta1-induced hepatic stellate cell proliferation by targeting SMAD4. Cell Signal. 2012;24:1923-30 pubmed publisher
    ..Bioinformatics analyses predict that SMAD4 is the potential target of miR-146a...
  22. Fortin J, Boehm U, Deng C, Treier M, Bernard D. Follicle-stimulating hormone synthesis and fertility depend on SMAD4 and FOXL2. FASEB J. 2014;28:3396-410 pubmed publisher
    ..Here, using conditional gene-targeting, we show that the canonical mediator of TGF? superfamily signaling, SMAD4, is absolutely required for normal FSH synthesis in both male and female mice...
  23. Zhang Y, Hu J, Liu X, Wang R, Xu R. [Location studies of Smad4 protein in the rat testis during postnatal development]. Shi Yan Sheng Wu Xue Bao. 2002;35:7-14 pubmed
    ..In order to shed light on the mechanisms of TGF-beta action in the testis,we examined the expression and function of Smad4 protein, the common-mediator Smads, which is one of intracellular signaling molecules of TGF-beta superfamily ..
  24. Roth S, Johansson M, Loukola A, Peltomaki P, Jarvinen H, Mecklin J, et al. Mutation analysis of SMAD2, SMAD3, and SMAD4 genes in hereditary non-polyposis colorectal. J Med Genet. 2000;37:298-300 pubmed
  25. Bénazet J, Pignatti E, Nugent A, Unal E, Laurent F, Zeller R. Smad4 is required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors in mouse limb buds. Development. 2012;139:4250-60 pubmed publisher
    b>SMAD4 is an essential mediator of canonical TGF?/BMP signal transduction and we inactivated Smad4 in mouse limb buds from early stages onward to study its functions in the mesenchyme...
  26. Wong H, Lemoine N. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat Rev Gastroenterol Hepatol. 2009;6:412-22 pubmed publisher
    ..This Review describes some of the important developments and targeted agents for pancreatic cancer that have been tested in clinical trials. ..
  27. Zhang J, Pho V, Bonasera S, Holtzman J, Tang A, Hellmuth J, et al. Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons. Nat Neurosci. 2007;10:77-86 pubmed
    ..These data underscore the importance of the TGFbeta-Smad-HIPK2 pathway in the survival of DA neurons and its potential as a therapeutic target for promoting DA neuron survival during neurodegeneration. ..
  28. Piestrzeniewicz Ulanska D, Brys M, Semczuk A, Rechberger T, Jakowicki J, Krajewska W. TGF-beta signaling is disrupted in endometrioid-type endometrial carcinomas. Gynecol Oncol. 2004;95:173-80 pubmed
    ..cascade components, including TGF-beta receptor type I (TGF beta RI) and type II (TGF beta RII), SMAD2, SMAD3, SMAD4, and clinicopathological features--tumor grade, FIGO classification, and depth of myometrial invasion--of type I (..
  29. Shioda T, Lechleider R, Dunwoodie S, Li H, Yahata T, de Caestecker M, et al. Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator. Proc Natl Acad Sci U S A. 1998;95:9785-90 pubmed
    b>Smad4 plays a pivotal role in signal transduction of the transforming growth factor beta superfamily cytokines by mediating transcriptional activation of target genes...
  30. Wang J, Wang Y, Wang Y, Ma Y, Lan Y, Yang X. Transforming growth factor ?-regulated microRNA-29a promotes angiogenesis through targeting the phosphatase and tensin homolog in endothelium. J Biol Chem. 2013;288:10418-26 pubmed publisher
    ..MiR-29a was directly up-regulated by TGF-?/Smad4 signaling in human and mice endothelial cells...
  31. Hartwig S, Hu M, Cella C, Piscione T, Filmus J, Rosenblum N. Glypican-3 modulates inhibitory Bmp2-Smad signaling to control renal development in vivo. Mech Dev. 2005;122:928-38 pubmed
    ..models of branching morphogenesis, we demonstrated that BMP2 signals via its intracellular effectors, SMAD1 and SMAD4, to control UB cell proliferation and branching in a manner modulated by Glypican-3 (GPC3), a cell surface heparan ..
  32. Zhou X, Gao C, Huang W, Yang M, Chen G, Jiang L, et al. High glucose induces sumoylation of Smad4 via SUMO2/3 in mesangial cells. Biomed Res Int. 2014;2014:782625 pubmed publisher
    ..In the present study, we investigated the expression of SUMO (SUMO1 and SUMO2/3) and Smad4 and the interaction between SUMO and Smad4 in cultured rat mesangial cells induced by high glucose...
  33. Wang J, Xu N, Feng X, Hou N, Zhang J, Cheng X, et al. Targeted disruption of Smad4 in cardiomyocytes results in cardiac hypertrophy and heart failure. Circ Res. 2005;97:821-8 pubmed
    ..b>Smad4 is the central intracellular mediator of TGF-beta signaling...
  34. Gao Y, Yang G, Weng T, Du J, Wang X, Zhou J, et al. Disruption of Smad4 in odontoblasts causes multiple keratocystic odontogenic tumors and tooth malformation in mice. Mol Cell Biol. 2009;29:5941-51 pubmed publisher
    ..Here, we show that specific ablation of Smad4 in odontoblasts unexpectedly resulted in spontaneous KCOTs in mice...
  35. Horvath L, Henshall S, Kench J, Turner J, Golovsky D, Brenner P, et al. Loss of BMP2, Smad8, and Smad4 expression in prostate cancer progression. Prostate. 2004;59:234-42 pubmed
    ..This study aimed to characterize aspects of the BMP pathway in PC by assessing BMP2, Smad8, and Smad4 expression in normal, hyperplastic, and malignant prostate tissue, and to correlate findings with progression to ..
  36. Xu Y, Pasche B. TGF-beta signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet. 2007;16 Spec No 1:R14-20 pubmed
  37. Bornstein S, White R, Malkoski S, Oka M, Han G, Cleaver T, et al. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest. 2009;119:3408-19 pubmed publisher
    b>Smad4 is a central mediator of TGF-beta signaling, and its expression is downregulated or lost at the malignant stage in several cancer types...
  38. Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet. 2011;44:85-8 pubmed publisher
    ..Using exome sequencing of individuals with Myhre syndrome, we identified SMAD4 as a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic ..
  39. Gallione C, Aylsworth A, Beis J, Berk T, Bernhardt B, Clark R, et al. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A. 2010;152A:333-9 pubmed publisher
    ..JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT)...
  40. Denissova N, Pouponnot C, Long J, He D, Liu F. Transforming growth factor beta -inducible independent binding of SMAD to the Smad7 promoter. Proc Natl Acad Sci U S A. 2000;97:6397-402 pubmed previously identified by a PCR-based selection from random oligonucleotides by using recombinant Smad3 and Smad4. We demonstrate that on TGF-beta treatment, endogenous SMAD complex can bind to a Smad7 promoter DNA as short as ..
  41. Sunde J, Donninger H, Wu K, Johnson M, Pestell R, Rose G, et al. Expression profiling identifies altered expression of genes that contribute to the inhibition of transforming growth factor-beta signaling in ovarian cancer. Cancer Res. 2006;66:8404-12 pubmed advanced-stage ovarian cancers and, conversely, genes that enhance TGF-beta signaling (PCAF, TFE3, TGFBRII, and SMAD4) were down-regulated compared with the normal samples...
  42. Carr J, Dahdaleh F, Wang D, Howe J. Germline mutations in SMAD4 disrupt bone morphogenetic protein signaling. J Surg Res. 2012;174:211-4 pubmed publisher
    ..Germline mutations in the tumor suppressor gene SMAD4 account for approximately 20% of JP cases...
  43. Wilkinson D, Ogden S, Stratton S, Piechan J, Nguyen T, Smulian G, et al. A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and transcription repression of the alpha-fetoprotein gene. Mol Cell Biol. 2005;25:1200-12 pubmed
    ..ChIP assays show that TGF-beta1 stimulates p53, Smad4, P-Smad2 binding, and histone H3K9 deacetylation and methylation, at the SBE/p53RE...
  44. Inman G, Hill C. Stoichiometry of active smad-transcription factor complexes on DNA. J Biol Chem. 2002;277:51008-16 pubmed
    ..the receptor-regulated Smads (R-Smads), Smad2 and Smad3, which form hetero-oligomeric complexes with the co-Smad, Smad4, and translocate to the nucleus...
  45. Wu R, Zhang Y, Feng X, Derynck R. Heteromeric and homomeric interactions correlate with signaling activity and functional cooperativity of Smad3 and Smad4/DPC4. Mol Cell Biol. 1997;17:2521-8 pubmed
    ..Two homologs, the receptor-associated Smad3 and the tumor suppressor Smad4/DPC4, synergize to induce ligand-independent TGF-beta activities and are essential mediators of the natural TGF-..
  46. Subramanian S, Polikandriotis J, Kelm R, David J, Orosz C, Strauch A. Induction of vascular smooth muscle alpha-actin gene transcription in transforming growth factor beta1-activated myofibroblasts mediated by dynamic interplay between the Pur repressor proteins and Sp1/Smad coactivators. Mol Biol Cell. 2004;15:4532-43 pubmed
    ..Interplay between Pur repressor isoforms and Sp1 and Smad coactivators may regulate SMA enhancer output in TGFbeta1-activated myofibroblasts during episodes of wound repair and tissue remodeling. ..
  47. Rocha B, Colli S, Barcelos L, Gregório B, Sampaio F. Age-dependent expression of Pten and Smad4 genes in the urogenital system of Wistar rats. Acta Cir Bras. 2014;29 Suppl 1:34-8 pubmed
    To analyze Pten and Smad4 gene expression in the urogenital system of Wistar rats in differents ages. Pten and Smad4 mRNA expression was assessed in the bladder, ventral prostate, testis, ovaries, and uterus by real-time PCR...
  48. Zhou Y, Kato H, Shan D, Minami R, Kitazawa S, Matsuda T, et al. Involvement of mutations in the DPC4 promoter in endometrial carcinoma development. Mol Carcinog. 1999;25:64-72 pubmed
    ..Chloramphenicol acetyltransferase assays clearly demonstrated that the mutant promoters had the potential to suppress or silence DPC4 transcription, implicating the DPC4 gene in endometrial carcinoma. ..
  49. Zhang S, Fei T, Zhang L, Zhang R, Chen F, Ning Y, et al. Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation. Mol Cell Biol. 2007;27:4488-99 pubmed
    ..Finally, we provide evidence that Smad7 disrupts the formation of the TGF-beta-induced functional Smad-DNA complex. Our findings suggest that Smad7 inhibits TGF-beta signaling in the nucleus by a novel mechanism. ..
  50. Lin H, Wang H, Li Q, Liu D, Zhang X, Liu G, et al. Expression of Smad2 and Smad4, transforming growth factor-beta signal transducers in rat endometrium during the estrous cycle, pre-, and peri-implantation. Anim Reprod Sci. 2004;80:303-16 pubmed
    ..and implantation, we performed in situ hybridization to investigate the expression patterns of mRNAs for Smad2 and Smad4 in rat endometrium during the estrous cycle and on Days 0.5, 1.5, 2.5, 3.5, 4.5, 5.5, and 6.5 of pregnancy...
  51. Moskowitz I, Wang J, Peterson M, Pu W, MacKinnon A, Oxburgh L, et al. Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. [corrected]. Proc Natl Acad Sci U S A. 2011;108:4006-11 pubmed publisher
    ..but not a mutation causing secundum atrial septal defects (S52F), demonstrated impaired protein interactions with SMAD4, a transcription factor required for canonical bone morphogenetic protein/transforming growth factor-β (BMP/TGF-..
  52. Wang R, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2:399-409 pubmed
    ..Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most ..
  53. Takaku K, Oshima M, Miyoshi H, Matsui M, Seldin M, Taketo M. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell. 1998;92:645-56 pubmed
    The DPC4 (SMAD4) gene plays a key role in the TGFbeta signaling pathway. We inactivated its mouse homolog Dpc4 (Smad4). The homozygous mutants were embryonic lethal, whereas the heterozygotes showed no abnormality...
  54. Jones S, Zhang X, Parsons D, Lin J, Leary R, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801-6 pubmed publisher
    ..Dysregulation of these core pathways and processes through mutation can explain the major features of pancreatic tumorigenesis...
  55. Park D, Lee C, Sol M, Suh K, Yoon S, Kim J. Expression and localization of the transforming growth factor-beta type I receptor and Smads in preneoplastic lesions during chemical hepatocarcinogenesis in rats. J Korean Med Sci. 2003;18:510-9 pubmed
    ..We investigated expressions and localizations of TGR1, Smad2, Smad4, and Smad7 by using semi-quantitative RT-PCR and immunohistochemistry in preneoplastic lesions during rat chemical ..
  56. Labbe E, Silvestri C, Hoodless P, Wrana J, Attisano L. Smad2 and Smad3 positively and negatively regulate TGF beta-dependent transcription through the forkhead DNA-binding protein FAST2. Mol Cell. 1998;2:109-20 pubmed
    ..gsc promoter, but efficient transcriptional activation and assembly of a DNA-binding complex of FAST2, Smad2, and Smad4 requires an adjacent Smad4 site. Smad3 is closely related to Smad2 but suppresses activation of the gsc promoter...
  57. Schneiders D, Heger J, Best P, Michael Piper H, Taimor G. SMAD proteins are involved in apoptosis induction in ventricular cardiomyocytes. Cardiovasc Res. 2005;67:87-96 pubmed
    ..6% (p < 0.05 vs. control, n = 9). The SMAD complex is formed from SMAD4 and 3...
  58. Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, et al. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J. 1997;16:5353-62 pubmed
    ..Smad2 and Smad3 are structurally highly similar and mediate TGF-beta signals. Smad4 is distantly related to Smads 2 and 3, and forms a heteromeric complex with Smad2 after TGF-beta or activin ..
  59. Takaku K, Miyoshi H, Matsunaga A, Oshima M, Sasaki N, Taketo M. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res. 1999;59:6113-7 pubmed
    The SMAD4 (DPC4) gene was initially isolated as a candidate tumor suppressor from the convergent site of homozygous deletions on 18q in a panel of pancreatic carcinoma cell lines...
  60. Abrass C, Hansen K. Insulin-like growth factor-binding protein-5-induced laminin gamma1 transcription requires filamin A. J Biol Chem. 2010;285:12925-34 pubmed publisher
    ..These studies provide new insights into the mechanisms whereby IGFBP-5 and FLNa exert intranuclear effects. ..
  61. Gallione C, Repetto G, Legius E, Rustgi A, Schelley S, Tejpar S, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363:852-9 pubmed
    ..The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in MADH4 (encoding SMAD4) or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG (..
  62. Luan H, Yang L, Liu L, Liu S, Zhao X, Sui H, et al. Effects of platycodins on liver complications of type 2 diabetes. Mol Med Rep. 2014;10:1597-603 pubmed publisher
    ..The current study suggests that this therapeutic effect is mediated through the BMP?9/Smad?4 pathway. ..
  63. Pavio N, Battaglia S, Boucreux D, Arnulf B, Sobesky R, Hermine O, et al. Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-beta pathway. Oncogene. 2005;24:6119-32 pubmed
    ..These results suggest that during chronic infection, there is selection of viral variants that may promote cell transformation by providing, to clonally expanding cells, resistance to TGF-beta antiproliferative effects. ..
  64. Seno H, Oshima M, Ishikawa T, Oshima H, Takaku K, Chiba T, et al. Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc(Delta716) mouse intestinal polyps. Cancer Res. 2002;62:506-11 pubmed
    ..We scored MVD also in several compound mutants carrying Apc(Delta716), namely, mice with an additional mutation in Smad4, in which the polyps progress into invasive adenocarcinomas; mice with a cyclooxygenase (COX)-2 gene (Ptgs2) ..
  65. Baburajendran N, Jauch R, Tan C, Narasimhan K, Kolatkar P. Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers. Nucleic Acids Res. 2011;39:8213-22 pubmed publisher
    Smad proteins form multimeric complexes consisting of the 'common partner' Smad4 and receptor regulated R-Smads on clustered DNA binding sites...
  66. Heger J, Peters S, Piper H, Euler G. SMAD-proteins as a molecular switch from hypertrophy to apoptosis induction in adult ventricular cardiomyocytes. J Cell Physiol. 2009;220:515-23 pubmed publisher
    ..To test this hypothesis we infected isolated rat ventricular cardiomyocytes with adenovirus encoding SMAD4 (AdSMAD4) and investigated the impact of SMAD4 overexpression on the development of apoptosis and hypertrophy ..
  67. Si L, Shi J, Gao W, Zheng M, Liu L, Zhu J, et al. Smad4 mediated BMP2 signal is essential for the regulation of GATA4 and Nkx2.5 by affecting the histone H3 acetylation in H9c2 cells. Biochem Biophys Res Commun. 2014;450:81-6 pubmed publisher
    BMP2 signaling pathway plays critical roles during heart development, Smad4 encodes the only common Smad protein in mammals, which is a pivotal nuclear mediator...
  68. Morty R, Nejman B, Kwapiszewska G, Hecker M, Zakrzewicz A, Kouri F, et al. Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol. 2007;27:1072-8 pubmed
    ..BMP signaling and BMP-regulated physiological phenomena are perturbed in MCT-treated rats, lending solid support to the proposed roles for BMP signaling in the pathogenesis of human PAH. ..
  69. Okuyama N, Kiryu Seo S, Kiyama H. Altered expression of Smad family members in injured motor neurons of rat. Brain Res. 2007;1132:36-41 pubmed
    ..Immunohistochemistry and Western blotting analysis confirmed the alterations of Smad1, 2 and 4 in injured neurons. These results suggest that the Smad signaling may be important for nerve regeneration. ..
  70. Chen J, Fan X, Zhan X, Wang W. [Effect of Budesonide on Smad4, PDGF-A and PAI-1 in a rat model of pulmonary fibrosis]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2012;28:478-80 pubmed
    To observe the effect of Budesonide (BUD) on TGF-?1, PDGF-A, Smad4 and PAI-1 in lung tissue in pulmonary fibrosis rats...
  71. Sharff K, Song W, Luo X, Tang N, Luo J, Chen J, et al. Hey1 basic helix-loop-helix protein plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal progenitor cells. J Biol Chem. 2009;284:649-59 pubmed publisher
    ..Thus, our findings suggest that Hey1, through its interplay with Runx2, may play an important role in regulating BMP9-induced osteoblast lineage differentiation of MSCs. ..
  72. Liu F, Pouponnot C, Massague J. Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes. Genes Dev. 1997;11:3157-67 pubmed
    ..Smads 1 and 2 require association with the product of deleted in pancreatic carcinoma, locus 4 (DPC4), Smad4. We investigated the step at which Smad4 is required for transcriptional activation...
  73. Hua Y, Li S, Lai J, Liang L, Peng B, Liang H, et al. [Changes in TGF-beta1/Smads signaling pathway in rats with chemical hepatocarcinogenesis]. Nan Fang Yi Ke Da Xue Xue Bao. 2008;28:1848-52 pubmed
    ..The protein expressions of TGF-beta1, phosphorylated Smad2, Smad4 and Smad7 were detected in these rats with immunohistochemistry, and the mRNA expression of Smad4 was evaluated ..
  74. Zhang H, Akman H, Smith E, Zhao J, Murphy Ullrich J, Batuman O. Cellular response to hypoxia involves signaling via Smad proteins. Blood. 2003;101:2253-60 pubmed
    ..Autocrine regulation of TGF-beta2 production in hypoxia may involve cross-talk between Smad3 and HIF-1alpha signaling pathways, and could be an important mechanism by which endothelial cells respond to hypoxic stress. ..
  75. Topper J, Cai J, Qiu Y, Anderson K, Xu Y, Deeds J, et al. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc Natl Acad Sci U S A. 1997;94:9314-9 pubmed
  76. Ellis L, Warner D, Greene R, Pisano M. Interaction of Smads with collagen types I, III, and V. Biochem Biophys Res Commun. 2003;310:1117-23 pubmed
    ..Moreover, TGFbeta is a potent regulator of collagen synthesis and turnover during mammalian orofacial development. These data thus suggest an important means of feedback regulation of the TGFbeta signaling cascade. ..
  77. Gallione C, Richards J, Letteboer T, Rushlow D, Prigoda N, Leedom T, et al. SMAD4 mutations found in unselected HHT patients. J Med Genet. 2006;43:793-7 pubmed
    ..Mutations in SMAD4, another TGF-beta pathway member, are seen in patients with the combined syndrome of juvenile polyposis (JP) and ..
  78. Liu X, Sun S, Hassid A, Ostrom R. cAMP inhibits transforming growth factor-beta-stimulated collagen synthesis via inhibition of extracellular signal-regulated kinase 1/2 and Smad signaling in cardiac fibroblasts. Mol Pharmacol. 2006;70:1992-2003 pubmed
    ..the transcriptional coactivator CREB-binding protein 1 to transcriptional complexes containing Smad2, Smad3, and Smad4. Pharmacological inhibition of ERK completely blocked TGF-beta-stimulated collagen gene expression, but expression ..
  79. Mancini M, Verdi J, Conley B, Nicola T, Spicer D, Oxburgh L, et al. Endoglin is required for myogenic differentiation potential of neural crest stem cells. Dev Biol. 2007;308:520-33 pubmed
    ..These findings demonstrate a cell autonomous role for endoglin in smooth muscle cell specification contributing to vascular integrity. ..
  80. Dai C, Liu Y. Hepatocyte growth factor antagonizes the profibrotic action of TGF-beta1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF. J Am Soc Nephrol. 2004;15:1402-12 pubmed
    ..These results suggest that HGF specifically antagonizes the profibrotic action of TGF-beta1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF. ..
  81. Taketo M, Takaku K. Gastro-intestinal tumorigenesis in Smad4 mutant mice. Cytokine Growth Factor Rev. 2000;11:147-57 pubmed
    The SMAD4 gene plays a key role in the TGF-beta signaling pathway. We inactivated its mouse homolog Smad4. The homozygous mutants were embryonically lethal, whereas the heterozygotes were viable and fertile...
  82. Xie W, Mertens J, Reiss D, Rimm D, Camp R, Haffty B, et al. Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. Cancer Res. 2002;62:497-505 pubmed
    ..Moreover, only one of the cell lines failed to express Smad4. Among 456 cases of human breast carcinoma assembled in tissue microarrays, the majority (92%) expressed Smad2, ..
  83. Wilkinson D, Tsai W, Schumacher M, Barton M. Chromatin-bound p53 anchors activated Smads and the mSin3A corepressor to confer transforming-growth-factor-beta-mediated transcription repression. Mol Cell Biol. 2008;28:1988-98 pubmed publisher
    ..We propose that activation of TGF-beta signaling restores a dynamic interplay between p53 and TGF-beta effectors that cooperate to effectively target mSin3A to tumor marker AFP and reestablish transcription repression. ..