Smad4

Summary

Gene Symbol: Smad4
Description: SMAD family member 4
Alias: AW743858, D18Wsu70e, DPC4, Madh4, mothers against decapentaplegic homolog 4, MAD homolog 4, Smad 4, deletion target in pancreatic carcinoma 4 homolog, mothers against DPP homolog 4
Species: mouse
Products:     Smad4

Top Publications

  1. Xu X, Ehdaie B, Ohara N, Yoshino T, Deng C. Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice. Oncogene. 2010;29:674-86 pubmed publisher
    Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive...
  2. Biondi C, Das D, Howell M, Islam A, Bikoff E, Hill C, et al. Mice develop normally in the absence of Smad4 nucleocytoplasmic shuttling. Biochem J. 2007;404:235-45 pubmed
    b>Smad4 in partnership with R-Smads (receptor-regulated Smads) activates TGF-beta (transforming growth factor-beta)-dependent signalling pathways essential for early mouse development...
  3. Meng X, Huang X, Xiao J, Chung A, Qin W, Chen H, et al. Disruption of Smad4 impairs TGF-?/Smad3 and Smad7 transcriptional regulation during renal inflammation and fibrosis in vivo and in vitro. Kidney Int. 2012;81:266-79 pubmed publisher
    ..Following activation, these Smads form heteromeric complex with Smad4 and translocate into the nucleus to bind and regulate the expression of target genes...
  4. Yang X, Li C, Herrera P, Deng C. Generation of Smad4/Dpc4 conditional knockout mice. Genesis. 2002;32:80-1 pubmed
  5. Morikawa Y, Zehir A, Maska E, Deng C, Schneider M, Mishina Y, et al. BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways. Development. 2009;136:3575-84 pubmed publisher
    ..To determine if Alk3 signals through the canonical BMP pathway, Smad4 was deleted in the NC lineage...
  6. Kojima K, Vickers S, Adsay N, Jhala N, Kim H, Schoeb T, et al. Inactivation of Smad4 accelerates Kras(G12D)-mediated pancreatic neoplasia. Cancer Res. 2007;67:8121-30 pubmed
    ..almost uniformly present in early-stage disease, with subsequent inactivating mutations in p16(INK4A), p53, and SMAD4 occurring in more advanced lesions...
  7. 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 ..
  8. Karlsson G, Blank U, Moody J, Ehinger M, Singbrant S, Deng C, et al. Smad4 is critical for self-renewal of hematopoietic stem cells. J Exp Med. 2007;204:467-74 pubmed
    ..Working at a common level of convergence for all TGF-beta superfamily signals, Smad4 is key in orchestrating these effects...
  9. Xu X, Han J, Ito Y, Bringas P, Deng C, Chai Y. Ectodermal Smad4 and p38 MAPK are functionally redundant in mediating TGF-beta/BMP signaling during tooth and palate development. Dev Cell. 2008;15:322-9 pubmed publisher
    b>Smad4 is a central intracellular effector of TGF-beta signaling. Smad-independent TGF-beta pathways, such as those mediated by p38 MAPK, have been identified in cell culture systems, but their in vivo functional mechanisms remain unclear...
  10. Song L, Yan W, Chen X, Deng C, Wang Q, Jiao K. Myocardial smad4 is essential for cardiogenesis in mouse embryos. Circ Res. 2007;101:277-85 pubmed
    ..b>Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of transforming growth ..

Detail Information

Publications62

  1. Xu X, Ehdaie B, Ohara N, Yoshino T, Deng C. Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice. Oncogene. 2010;29:674-86 pubmed publisher
    Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive...
  2. Biondi C, Das D, Howell M, Islam A, Bikoff E, Hill C, et al. Mice develop normally in the absence of Smad4 nucleocytoplasmic shuttling. Biochem J. 2007;404:235-45 pubmed
    b>Smad4 in partnership with R-Smads (receptor-regulated Smads) activates TGF-beta (transforming growth factor-beta)-dependent signalling pathways essential for early mouse development...
  3. Meng X, Huang X, Xiao J, Chung A, Qin W, Chen H, et al. Disruption of Smad4 impairs TGF-?/Smad3 and Smad7 transcriptional regulation during renal inflammation and fibrosis in vivo and in vitro. Kidney Int. 2012;81:266-79 pubmed publisher
    ..Following activation, these Smads form heteromeric complex with Smad4 and translocate into the nucleus to bind and regulate the expression of target genes...
  4. Yang X, Li C, Herrera P, Deng C. Generation of Smad4/Dpc4 conditional knockout mice. Genesis. 2002;32:80-1 pubmed
  5. Morikawa Y, Zehir A, Maska E, Deng C, Schneider M, Mishina Y, et al. BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways. Development. 2009;136:3575-84 pubmed publisher
    ..To determine if Alk3 signals through the canonical BMP pathway, Smad4 was deleted in the NC lineage...
  6. Kojima K, Vickers S, Adsay N, Jhala N, Kim H, Schoeb T, et al. Inactivation of Smad4 accelerates Kras(G12D)-mediated pancreatic neoplasia. Cancer Res. 2007;67:8121-30 pubmed
    ..almost uniformly present in early-stage disease, with subsequent inactivating mutations in p16(INK4A), p53, and SMAD4 occurring in more advanced lesions...
  7. 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 ..
  8. Karlsson G, Blank U, Moody J, Ehinger M, Singbrant S, Deng C, et al. Smad4 is critical for self-renewal of hematopoietic stem cells. J Exp Med. 2007;204:467-74 pubmed
    ..Working at a common level of convergence for all TGF-beta superfamily signals, Smad4 is key in orchestrating these effects...
  9. Xu X, Han J, Ito Y, Bringas P, Deng C, Chai Y. Ectodermal Smad4 and p38 MAPK are functionally redundant in mediating TGF-beta/BMP signaling during tooth and palate development. Dev Cell. 2008;15:322-9 pubmed publisher
    b>Smad4 is a central intracellular effector of TGF-beta signaling. Smad-independent TGF-beta pathways, such as those mediated by p38 MAPK, have been identified in cell culture systems, but their in vivo functional mechanisms remain unclear...
  10. Song L, Yan W, Chen X, Deng C, Wang Q, Jiao K. Myocardial smad4 is essential for cardiogenesis in mouse embryos. Circ Res. 2007;101:277-85 pubmed
    ..b>Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of transforming growth ..
  11. 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. ..
  12. 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...
  13. Kim B, Li C, Qiao W, Mamura M, Kasprzak B, Kasperczak B, et al. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature. 2006;441:1015-9 pubmed
    b>SMAD4 (MAD homologue 4 (Drosophila)), also known as DPC4 (deleted in pancreatic cancer), is a tumour suppressor gene that encodes a central mediator of transforming growth factor-beta signalling...
  14. Qi X, Yang G, Yang L, Lan Y, Weng T, Wang J, et al. Essential role of Smad4 in maintaining cardiomyocyte proliferation during murine embryonic heart development. Dev Biol. 2007;311:136-46 pubmed
    ..The intracellular factor Smad4 plays a pivotal role in mediating TGF-beta/BMP signal transduction in the nucleus...
  15. Li W, Qiao W, Chen L, Xu X, Yang X, Li D, et al. Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice. Development. 2003;130:6143-53 pubmed
    b>Smad4 is a central mediator for TGFbeta signals, which play important functions in many biological processes...
  16. Bardeesy N, Cheng K, Berger J, Chu G, Pahler J, Olson P, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006;20:3130-46 pubmed
    b>SMAD4 is inactivated in the majority of pancreatic ductal adenocarcinomas (PDAC) with concurrent mutational inactivation of the INK4A/ARF tumor suppressor locus and activation of the KRAS oncogene...
  17. Kitamura T, Kometani K, Hashida H, Matsunaga A, Miyoshi H, Hosogi H, et al. SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. Nat Genet. 2007;39:467-75 pubmed
    Inactivation of TGF-beta family signaling is implicated in colorectal tumor progression. Using cis-Apc(+/Delta716) Smad4(+/-) mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF-beta family ..
  18. Alejandre Alcazar M, Michiels Corsten M, Vicencio A, Reiss I, Ryu J, de Krijger R, et al. TGF-beta signaling is dynamically regulated during the alveolarization of rodent and human lungs. Dev Dyn. 2008;237:259-69 pubmed
    ..TGF-beta receptors Acvrl1, Tgfbr1, Tgfbr2, Tgfbr3, and endoglin, and the intracellular messengers Smad2, Smad3, Smad4, Smad6, and Smad7 were noted as mouse and human lungs progressed through the canalicular, saccular, and alveolar ..
  19. 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...
  20. Waldrip W, Bikoff E, Hoodless P, Wrana J, Robertson E. Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell. 1998;92:797-808 pubmed
    ..Chimera experiments demonstrate these essential activities are contributed by the extraembryonic tissues. Thus, the extraembryonic tissues play critical roles in establishing the body plan during early mouse development. ..
  21. Xu X, Brodie S, Yang X, Im Y, Parks W, Chen L, et al. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Oncogene. 2000;19:1868-74 pubmed
    The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cancer, is a central mediator of TGF-beta signaling...
  22. Hoot K, Lighthall J, Han G, Lu S, Li A, Ju W, et al. Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression. J Clin Invest. 2008;118:2722-32 pubmed publisher
    ..b>Smad4-/- mouse epidermis develops spontaneous skin squamous cell carcinomas (SCCs), and Smad3-/- mice are resistant to ..
  23. Owens P, Bazzi H, Engelking E, Han G, Christiano A, Wang X. Smad4-dependent desmoglein-4 expression contributes to hair follicle integrity. Dev Biol. 2008;322:156-66 pubmed publisher
    We have previously shown that keratinocyte-specific deletion of Smad4, a TGFbeta/Activin/BMP signaling mediator, results in a progressive alopecia...
  24. Qiao W, Li A, Owens P, Xu X, Wang X, Deng C. Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin. Oncogene. 2006;25:207-17 pubmed
    b>Smad4 is the common mediator for TGFbeta signals, which play important functions in many biological processes...
  25. Yang L, Mao C, Teng Y, Li W, Zhang J, Cheng X, et al. Targeted disruption of Smad4 in mouse epidermis results in failure of hair follicle cycling and formation of skin tumors. Cancer Res. 2005;65:8671-8 pubmed
    b>Smad4 is the common mediator of transforming growth factor-beta (TGF-beta) superfamily signaling, which functions in diverse developmental processes in mammals...
  26. Ding Z, Wu C, Chu G, Xiao Y, Ho D, Zhang J, et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011;470:269-73 pubmed publisher
    ..epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGF?/BMP-SMAD4 signalling axis...
  27. Mao X, Debenedittis P, Sun Y, Chen J, Yuan K, Jiao K, et al. Vascular smooth muscle cell Smad4 gene is important for mouse vascular development. Arterioscler Thromb Vasc Biol. 2012;32:2171-7 pubmed publisher
    b>Smad4 is a central mediator of transforming growth factor-?/bone morphogenetic protein signaling that controls numerous developmental processes as well as homeostasis in the adult...
  28. Li F, Lan Y, Wang Y, Wang J, Yang G, Meng F, et al. Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. Dev Cell. 2011;20:291-302 pubmed publisher
    ..Here, we report that disruption of Smad4, the central intracellular mediator of transforming growth factor-? (TGF-?) signaling, specifically in the ..
  29. Tripathi P, Wang Y, Casey A, Chen F. Absence of canonical Smad signaling in ureteral and bladder mesenchyme causes ureteropelvic junction obstruction. J Am Soc Nephrol. 2012;23:618-28 pubmed publisher
    ..To study the molecular mechanisms that modulate ureteral development, we inactivated Smad4, the common Smad critical for transcriptional responses to TGF-? and Bmp signaling, in the ureteral and bladder ..
  30. 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...
  31. Tan X, Weng T, Zhang J, Wang J, Li W, Wan H, et al. Smad4 is required for maintaining normal murine postnatal bone homeostasis. J Cell Sci. 2007;120:2162-70 pubmed
    Transforming growth factor beta (TGFbeta) is a multifunctional cytokine involved in skeletal development. Smad4 is the central intracellular mediator of TGFbeta signaling...
  32. Yang X, Li C, Xu X, Deng C. The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice. Proc Natl Acad Sci U S A. 1998;95:3667-72 pubmed
    ..The tumor suppressor SMAD4, also known as DPC4, is believed to be an essential factor that mediates TGF-beta signals...
  33. Büchmann Møller S, Miescher I, John N, Krishnan J, Deng C, Sommer L. Multiple lineage-specific roles of Smad4 during neural crest development. Dev Biol. 2009;330:329-38 pubmed publisher
    ..To address these issues, we conditionally deleted Smad4 in the neural crest, thus inactivating all canonical TGFbeta factor signaling...
  34. Huss D, Winger R, Cox G, Guerau de Arellano M, Yang Y, Racke M, et al. TGF-? signaling via Smad4 drives IL-10 production in effector Th1 cells and reduces T-cell trafficking in EAE. Eur J Immunol. 2011;41:2987-96 pubmed publisher
    ..Additionally, TGF-? signaling causes binding of Smad4 to the IL-10 promoter, providing molecular evidence for TGF-?-mediated IL-10 production from Th1 effector cells...
  35. 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...
  36. Vincent S, Dunn N, Hayashi S, Norris D, Robertson E. Cell fate decisions within the mouse organizer are governed by graded Nodal signals. Genes Dev. 2003;17:1646-62 pubmed
    ..These findings conclusively demonstrate that graded Nodal/Smad2 signals govern allocation of the axial mesendoderm precursors that selectively give rise to the ADE and PCP mesoderm...
  37. Hohenstein P, Molenaar L, Elsinga J, Morreau H, van der Klift H, Struijk A, et al. Serrated adenomas and mixed polyposis caused by a splice acceptor deletion in the mouse Smad4 gene. Genes Chromosomes Cancer. 2003;36:273-82 pubmed
    ..here referred to as Sad (serrated adenomas), caused by a spontaneously risen splice site mutation in the murine Smad4 gene. The Sad chromosomal region was identified by genetic linkage and loss of heterozygosity (LOH) analysis...
  38. Hahn J, Falck V, Jirik F. Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice. J Clin Invest. 2011;121:4030-42 pubmed publisher
    ..Here, we employed two conditional mutagenesis systems to delete the TGF-? signaling pathway component Smad4 in T cells and observed the spontaneous development of massive polyps within the gastroduodenal regions of mice...
  39. Yang X, Nurieva R, Martinez G, Kang H, Chung Y, Pappu B, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008;29:44-56 pubmed publisher
    ..Although TGF-beta receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation...
  40. Nie X, Deng C, Wang Q, Jiao K. Disruption of Smad4 in neural crest cells leads to mid-gestation death with pharyngeal arch, craniofacial and cardiac defects. Dev Biol. 2008;316:417-30 pubmed publisher
    TGFbeta/BMP signaling pathways are essential for normal development of neural crest cells (NCCs). Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of TGFbeta/BMP signaling...
  41. Lan Y, Liu B, Yao H, Li F, Weng T, Yang G, et al. Essential role of endothelial Smad4 in vascular remodeling and integrity. Mol Cell Biol. 2007;27:7683-92 pubmed
    ..To investigate the role of endothelial Smad4 in vascular development, we deleted the Smad4 gene specifically in ECs using the Cre-LoxP system...
  42. Sirard C, Kim S, Mirtsos C, Tadich P, Hoodless P, Itie A, et al. Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor beta-related signaling. J Biol Chem. 2000;275:2063-70 pubmed
    The tumor suppressor gene Smad4 has been proposed to be a common mediator of transforming growth factor beta (TGFbeta)-related signaling pathways...
  43. Salazar V, Zarkadis N, Huang L, Norris J, Grimston S, Mbalaviele G, et al. Embryonic ablation of osteoblast Smad4 interrupts matrix synthesis in response to canonical Wnt signaling and causes an osteogenesis-imperfecta-like phenotype. J Cell Sci. 2013;126:4974-84 pubmed publisher
    ..interactions between bone morphogenic protein (BMP) and canonical Wnt signaling during skeletal growth, we ablated Smad4, a key component of the TGF-?-BMP pathway, in Osx1(+) cells in mice...
  44. 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) ..
  45. Hoot K, Oka M, Han G, Bottinger E, Zhang Q, Wang X. HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion. J Clin Invest. 2010;120:3606-16 pubmed publisher
    ..On the Hgf promoter, Smad2 was mainly associated with transcriptional corepressors, whereas Smad4 was mainly associated with the transcriptional coactivator CREB-binding protein (CBP/p300)...
  46. Jia Q, McDill B, Li S, Deng C, Chang C, Chen F. Smad signaling in the neural crest regulates cardiac outflow tract remodeling through cell autonomous and non-cell autonomous effects. Dev Biol. 2007;311:172-84 pubmed
    ..Here, we show that mice lacking Smad4 in NCCs have persistent truncus arteriosus (PTA), severe OFT cushion hypoplasia, defective OFT elongation, and ..
  47. Chen Y, Hsiao P, Weng C, Kuo K, Kuo T, Wu D, et al. SMAD4 loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells. BMC Cancer. 2014;14:181 pubmed publisher
    b>SMAD4 is a gastrointestinal malignancy-specific tumor suppressor gene found mutated in one third of colorectal cancer specimens and half of pancreatic tumors...
  48. Ko S, Chung I, Xu X, Oka S, Zhao H, Cho E, et al. Smad4 is required to regulate the fate of cranial neural crest cells. Dev Biol. 2007;312:435-47 pubmed
    b>Smad4 is the central mediator for TGF-beta/BMP signals, which are involved in regulating cranial neural crest (CNC) cell formation, migration, proliferation and fate determination...
  49. Zhou Y, Zhao M, Li D, Shimazu K, Sakata K, Deng C, et al. Cerebellar deficits and hyperactivity in mice lacking Smad4. J Biol Chem. 2003;278:42313-20 pubmed
    b>Smad4 is a central mediator of TGF-beta signals, which are known to play essential roles in many biological processes...
  50. Sirard C, de la Pompa J, Elia A, Itie A, Mirtsos C, Cheung A, et al. The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev. 1998;12:107-19 pubmed
    Mutations in the SMAD4/DPC4 tumor suppressor gene, a key signal transducer in most TGFbeta-related pathways, are involved in 50% of pancreatic cancers. Homozygous Smad4 mutant mice die before day 7.5 of embryogenesis...
  51. Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A, Grady W, et al. Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell. 2007;11:229-43 pubmed
    ..We show here that concomitant expression of Kras(G12D) and haploinsufficiency of the Smad4/Dpc4 tumor suppressor gene engenders a distinct class of pancreatic tumors, mucinous cystic neoplasms (MCNs), ..
  52. Weinstein M, Yang X, Deng C. Functions of mammalian Smad genes as revealed by targeted gene disruption in mice. Cytokine Growth Factor Rev. 2000;11:49-58 pubmed
    ..These experiments have shown that Smad2 and Smad4 are needed for gastrulation, Smad5 for angiogenesis, and Smad3 for establishment of the mucosal immune response ..
  53. Alberici P, Jagmohan Changur S, De Pater E, van der Valk M, Smits R, Hohenstein P, et al. Smad4 haploinsufficiency in mouse models for intestinal cancer. Oncogene. 2006;25:1841-51 pubmed
    The Smad4(+/E6sad) mouse carries a null mutation in the endogenous Smad4 gene resulting in serrated adenomas and mixed polyposis of the upper gastrointestinal (GI) tract with 100% penetrance...
  54. Freeman T, Smith J, Chen X, Washington M, Roland J, Means A, et al. Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of ?-catenin. Gastroenterology. 2012;142:562-571.e2 pubmed publisher
    ..We investigated the effects of loss of the transcription factor Smad4 on levels of ?-catenin messenger RNA (mRNA) and Wnt signaling...
  55. 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...
  56. Heldin C, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390:465-71 pubmed
    ..cell-surface receptors that have serine/threonine kinase activity, then they oligomerize with the common mediator Smad4 and translocate to the nucleus where they direct transcription to effect the cell's response to TGF-beta...
  57. Nolting J, Daniel C, Reuter S, Stuelten C, Li P, Sucov H, et al. Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines. J Exp Med. 2009;206:2131-9 pubmed publisher
    ..Interleukin (IL)-6 strongly reduced RAR alpha expression levels such that a deficiency of the predominant RAR alpha 1 isoform leaves too little RAR alpha 2 for RA to inhibit the generation of Th17 cells in the presence of IL-6. ..
  58. Taketo M, Takaku K. Gastrointestinal tumorigenesis in Smad4 (Dpc4) mutant mice. Hum Cell. 2000;13:85-95 pubmed
    The SMAD4 (Dpc4) gene plays a key role in the TGF-beta signaling pathway. We recently inactivated the mouse homolog Smad4. The homozygous mutants were embryonic lethals, whereas the heterozygotes were viable and fertile...
  59. Moon Y, Yun C, Choi H, Ka S, Kim J, Park B, et al. Smad4 controls bone homeostasis through regulation of osteoblast/osteocyte viability. Exp Mol Med. 2016;48:e256 pubmed publisher
    Regulation of osteoblast and osteocyte viability is essential for bone homeostasis. Smad4, a major transducer of bone morphogenetic protein and transforming growth factor-β signaling pathways, regulates apoptosis in various cell types ..
  60. Meng F, Shi L, Cheng X, Hou N, Wang Y, Teng Y, et al. Surfactant protein A promoter directs the expression of Cre recombinase in brain microvascular endothelial cells of transgenic mice. Matrix Biol. 2007;26:54-7 pubmed
    ..5, indicating that the subpopulation of ECs in brain could be molecularly defined at early embryonic stages. The use of SP-A-Cre mice should facilitate analysis of gene function in the brain ECs. ..
  61. Liu G, Lin H, Zhang X, Li Q, Wang H, Qian D, et al. Expression of Smad2 and Smad4 in mouse uterus during the oestrous cycle and early pregnancy. Placenta. 2004;25:530-7 pubmed
    SMAD2 and SMAD4 are intracellular transducers of TGF-beta superfamily...
  62. Narula A, Kilen S, Ma E, Kroeger J, Goldberg E, Woodruff T. Smad4 overexpression causes germ cell ablation and leydig cell hyperplasia in transgenic mice. Am J Pathol. 2002;161:1723-34 pubmed
    ..The tumor suppressor gene, Smad4, is a common mediator of TGF-beta, activin, and bone morphogenetic protein-mediated signaling pathways...