Smad4

Summary

Gene Symbol: Smad4
Description: SMAD family member 4
Alias: DPC4, JIP, MADH4, MYHRS, mothers against decapentaplegic homolog 4, MAD homolog 4, SMAD, mothers against DPP homolog 4, deleted in pancreatic carcinoma locus 4, deletion target in pancreatic carcinoma 4, mothers against decapentaplegic, Drosophila, homolog of, 4
Species: human
Products:     Smad4

Top Publications

  1. Baldus S, Schwarz E, Lohrey C, Zapatka M, Landsberg S, Hahn S, et al. Smad4 deficiency in cervical carcinoma cells. Oncogene. 2005;24:810-9 pubmed
    ..Since the TGF-beta response is mediated by Smad proteins and the tumor suppressor gene Smad4 resides at 18q21, we have analysed the Smad4 gene for cervical cancer-associated alterations in cell lines and ..
  2. Jazag A, Ijichi H, Kanai F, Imamura T, Guleng B, Ohta M, et al. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference and gene expression profiles induced by transforming growth factor-beta. Oncogene. 2005;24:662-71 pubmed
    ..The Smad4 gene is mutated or deleted in 50% of pancreatic cancers...
  3. Hata A, Lagna G, Massague J, Hemmati Brivanlou A. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 1998;12:186-97 pubmed
    Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription...
  4. Papageorgis P, Cheng K, Ozturk S, Gong Y, Lambert A, Abdolmaleky H, et al. Smad4 inactivation promotes malignancy and drug resistance of colon cancer. Cancer Res. 2011;71:998-1008 pubmed publisher
    b>SMAD4 is localized to chromosome 18q21, a frequent site for loss of heterozygosity in advanced stage colon cancers...
  5. Howe J, Sayed M, Ahmed A, Ringold J, Larsen Haidle J, Merg A, et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet. 2004;41:484-91 pubmed
    ..We have identified mutations in two genes causing JP, MADH4 and bone morphogenetic protein receptor 1A (BMPR1A): both are involved in bone morphogenetic protein (BMP) ..
  6. Hiwatashi K, Ueno S, Sakoda M, Kubo F, Tateno T, Kurahara H, et al. Strong Smad4 expression correlates with poor prognosis after surgery in patients with hepatocellular carcinoma. Ann Surg Oncol. 2009;16:3176-82 pubmed publisher
    ..The Smad4 protein is the downstream mediator of TGF-beta...
  7. He W, Dorn D, Erdjument Bromage H, Tempst P, Moore M, Massague J. Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway. Cell. 2006;125:929-41 pubmed
    ..Formation of transcription regulatory complexes by the association of Smad4 with receptor-phosphorylated Smads 2 and 3 is a central event in the canonical TGFbeta pathway...
  8. Ke Z, Zhang X, Ma L, Wang L. Deleted in pancreatic carcinoma locus 4/Smad4 participates in the regulation of apoptosis by affecting the Bcl-2/Bax balance in non-small cell lung cancer. Hum Pathol. 2008;39:1438-45 pubmed publisher
    b>Deleted in pancreatic carcinoma locus 4 influences tumorigenesis and tumor progression by various mechanisms, including apoptosis...
  9. Long J, Matsuura I, He D, Wang G, Shuai K, Liu F. Repression of Smad transcriptional activity by PIASy, an inhibitor of activated STAT. Proc Natl Acad Sci U S A. 2003;100:9791-6 pubmed
    ..In an effort to identify Smad-interacting proteins by a yeast three-hybrid screen with Smad3 and Smad4 as baits, we identified PIASy, a member of the PIAS family...

More Information

Publications79

  1. Aitchison A, Veerakumarasivam A, Vias M, Kumar R, Hamdy F, Neal D, et al. Promoter methylation correlates with reduced Smad4 expression in advanced prostate cancer. Prostate. 2008;68:661-74 pubmed publisher
    ..A transducer of TGF-beta signaling known as Mothers against decapentaplegic homologue 4 (Smad4) is a known tumor suppressor found on chromosome 18q21...
  2. Crane C, Varadhachary G, Yordy J, Staerkel G, Javle M, Safran H, et al. Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. J Clin Oncol. 2011;29:3037-43 pubmed publisher
    ..Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression. Median overall survival time was 19.2 months (95% CI, 14.2 to 24...
  3. Wang L, Kim S, Lee J, Choi Y, Kim Y, Park T, et al. Inactivation of SMAD4 tumor suppressor gene during gastric carcinoma progression. Clin Cancer Res. 2007;13:102-10 pubmed
    Mothers against decapentaplegic homologue 4 (SMAD4) is a tumor suppressor gene associated with gastrointestinal carcinogenesis...
  4. Lee P, Chang C, Liu D, Derynck R. Sumoylation of Smad4, the common Smad mediator of transforming growth factor-beta family signaling. J Biol Chem. 2003;278:27853-63 pubmed
    ..Receptor-activated Smads combine with a common Smad4 to translocate into the nucleus where they cooperate with other transcription factors to activate or repress ..
  5. Yao G, Yin M, Lian J, Tian H, Liu L, Li X, et al. MicroRNA-224 is involved in transforming growth factor-beta-mediated mouse granulosa cell proliferation and granulosa cell function by targeting Smad4. Mol Endocrinol. 2010;24:540-51 pubmed publisher
    ..The ectopic expression of miR-224 can enhance TGF-beta1-induced GC proliferation through targeting Smad4. Inhibition of endogenous miR-224 partially suppressed GC proliferation induced by TGF-beta1...
  6. Romero D, Iglesias M, Vary C, Quintanilla M. Functional blockade of Smad4 leads to a decrease in beta-catenin levels and signaling activity in human pancreatic carcinoma cells. Carcinogenesis. 2008;29:1070-6 pubmed publisher
    ..Our previous studies in murine keratinocytes led to the identification of a cooperation between oncogenic Ras and Smad4 inactivation during malignant progression...
  7. Tian X, Du H, Fu X, Li K, Li A, Zhang Y. Smad4 restoration leads to a suppression of Wnt/beta-catenin signaling activity and migration capacity in human colon carcinoma cells. Biochem Biophys Res Commun. 2009;380:478-83 pubmed publisher
    Recent studies have reported that Smad4 has a TGF-beta-independent function as a tumor suppressor in cooperating with beta-catenin/Lef to regulate target gene expression...
  8. Agricola E, Randall R, Gaarenstroom T, Dupont S, Hill C. Recruitment of TIF1? to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities. Mol Cell. 2011;43:85-96 pubmed publisher
    ..TIF1?'s ability to ubiquitinate its substrate Smad4 requires its PHD finger-bromodomain, as does its transcriptional repressor activity...
  9. Hesling C, Fattet L, Teyre G, Jury D, Gonzalo P, Lopez J, et al. Antagonistic regulation of EMT by TIF1? and Smad4 in mammary epithelial cells. EMBO Rep. 2011;12:665-72 pubmed publisher
    ..A strong EMT increase was observed in TIF1?-silenced cells after TGF-?1 treatment, whereas Smad4 inactivation completely blocked this process...
  10. Iacobuzio Donahue C, Fu B, Yachida S, Luo M, Abe H, Henderson C, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806-13 pubmed publisher
    ..diagnosis, patterns of failure (locally destructive v metastatic disease) and the status of the KRAS2, TP53, and DPC4 genes...
  11. Koinuma D, Tsutsumi S, Kamimura N, Imamura T, Aburatani H, Miyazono K. Promoter-wide analysis of Smad4 binding sites in human epithelial cells. Cancer Sci. 2009;100:2133-42 pubmed publisher
    b>Smad4, the common partner Smad, is a key molecule in transforming growth factor-beta (TGF-beta) family signaling...
  12. Zhao S, Wang Y, Cao L, Ouellette M, Freeman J. Expression of oncogenic K-ras and loss of Smad4 cooperate to induce the expression of EGFR and to promote invasion of immortalized human pancreas ductal cells. Int J Cancer. 2010;127:2076-87 pubmed publisher
    ..In our study, we examined whether activating mutations of K-ras and loss of Smad4 play a role in causing the aberrant expression of PTKRs...
  13. D Inzeo S, Nicolussi A, Ricci A, Mancini P, Porcellini A, Nardi F, et al. Role of reduced expression of SMAD4 in papillary thyroid carcinoma. J Mol Endocrinol. 2010;45:229-44 pubmed publisher
    ..The deficiencies of SMAD4 are responsible to accelerate the malignant progression of neoplastic lesions in several types of tumors...
  14. Zhang L, Duan C, Binkley C, Li G, Uhler M, Logsdon C, et al. A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A. Mol Cell Biol. 2004;24:2169-80 pubmed
    ..Taken together, these data indicate an important and previously unrecognized interaction between the TGFbeta and PKA signaling pathways. ..
  15. Oshima M, Okano K, Muraki S, Haba R, Maeba T, Suzuki Y, et al. Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann Surg. 2013;258:336-46 pubmed publisher
    ..study was to clarify the clinical implications of the status of the 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4)...
  16. Ottenhof N, Morsink F, Ten Kate F, Van Noorden C, Offerhaus G. Multivariate analysis of immunohistochemical evaluation of protein expression in pancreatic ductal adenocarcinoma reveals prognostic significance for persistent Smad4 expression only. Cell Oncol (Dordr). 2012;35:119-26 pubmed publisher
    ..analysis included clinicopathological parameters and protein expression examined by immunohistochemistry of p53, Smad4, Axl, ALDH, MSH2, MSH6, MLH1 and PMS2. Lymph node ratio <0.2 (p?=?0.004), tumor free resection margins (p?=?0...
  17. Häger M, Pedersen C, Larsen M, Andersen M, Hother C, Grønbæk K, et al. MicroRNA-130a-mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-?1 stimulation in granulocytic precursors. Blood. 2011;118:6649-59 pubmed publisher
    b>Smad4 is important in the TGF-? pathway and required for transcriptional activation and inhibition of cell growth after TGF-?1 stimulation...
  18. Hua Z, Zhang Y, Hu X, Jia Z. Loss of DPC4 expression and its correlation with clinicopathological parameters in pancreatic carcinoma. World J Gastroenterol. 2003;9:2764-7 pubmed
    b>DPC4 is a tumor suppressor gene on chromosome 18q21.1 that has high mutant frequencies in pancreatic carcinogenesis...
  19. Kloth J, Kenter G, Spijker H, Uljee S, Corver W, Jordanova E, et al. Expression of Smad2 and Smad4 in cervical cancer: absent nuclear Smad4 expression correlates with poor survival. Mod Pathol. 2008;21:866-75 pubmed publisher
    Alterations in transforming growth factor-beta signaling, due to a decrease in Smad2 and especially Smad4 expression, has primarily been reported in pancreatic and colorectal cancers, although loss of the chromosomal region 18q21...
  20. Wang Y, Li W, Zang X, Chen N, Liu T, Tsonis P, et al. MicroRNA-204-5p regulates epithelial-to-mesenchymal transition during human posterior capsule opacification by targeting SMAD4. Invest Ophthalmol Vis Sci. 2013;54:323-32 pubmed publisher
    ..The expression of SMAD4, phospho-SMAD2/3, and a panel of EMT markers was detected by Western blot and quantitative RT-PCR...
  21. Zboralski D, Böckmann M, Zapatka M, Hoppe S, Schöneck A, Hahn S, et al. Divergent mechanisms underlie Smad4-mediated positive regulation of the three genes encoding the basement membrane component laminin-332 (laminin-5). BMC Cancer. 2008;8:215 pubmed publisher
    Functional inactivation of the tumor suppressor Smad4 in colorectal and pancreatic carcinogenesis occurs coincident with the transition to invasive growth...
  22. Yan J, Fang Y, Ding L, Zhu J, Lu Q, Huang C, et al. Regulation of large-scale chromatin unfolding by Smad4. Biochem Biophys Res Commun. 2004;315:330-5 pubmed
    The tumor suppressor Smad4 plays a critical role in the transforming growth factor-beta (TGF-beta signaling pathway. Smad4 is an essential component of transcriptional complexes mediating the activation of Smad-dependent target genes...
  23. Li H, Sekine M, Seng S, Avraham S, Avraham H. BRCA1 interacts with Smad3 and regulates Smad3-mediated TGF-beta signaling during oxidative stress responses. PLoS ONE. 2009;4:e7091 pubmed publisher
    ..expression of Smad3 protein in a dose-dependent manner, while silencing of WT-BRCA1 by siRNA decreased Smad3 and Smad4 interaction induced by TGF-beta in MCF-7 breast cancer cells...
  24. Isaksson Mettävainio M, Palmqvist R, Dahlin A, Van Guelpen B, Rutegård J, Oberg A, et al. High SMAD4 levels appear in microsatellite instability and hypermethylated colon cancers, and indicate a better prognosis. Int J Cancer. 2012;131:779-88 pubmed publisher
    ..b>SMAD4, located on chromosome 18q, has been thoroughly investigated during the last years...
  25. Zhong D, Morikawa A, Guo L, Colpaert C, Xiong L, Nassar A, et al. Homozygous deletion of SMAD4 in breast cancer cell lines and invasive ductal carcinomas. Cancer Biol Ther. 2006;5:601-7 pubmed
    Inactivation of TGF-beta/SMAD4 signaling was postulated to play an important role in breast cancer development...
  26. He S, Zhao Z, Wang Y, Zhao J, Wang L, Hou F, et al. Reduced expression of SMAD4 in gliomas correlates with progression and survival of patients. J Exp Clin Cancer Res. 2011;30:70 pubmed publisher
    To examine the expression of SMAD4 at gene and protein levels in glioma samples with different WHO grades and its association with survival. Two hundreds fifty-two glioma specimens and 42 normal control tissues were collected...
  27. Pyatt R, Pilarski R, Prior T. Mutation screening in juvenile polyposis syndrome. J Mol Diagn. 2006;8:84-8 pubmed
    ..Germline mutations have been identified in MADH4 and BMPR1A, aiding in presymptomatic genetic testing...
  28. Zhong H, Wang H, Yang S, Zhong J, Wang T, Wang C, et al. Targeting Smad4 links microRNA-146a to the TGF-beta pathway during retinoid acid induction in acute promyelocytic leukemia cell line. Int J Hematol. 2010;92:129-35 pubmed publisher
    ..Direct interaction between miR146a and its predictive target gene Smad4 were confirmed by Luciferase assay...
  29. Chang C, Lin D, Fang H, Chen R, Shih H. Daxx mediates the small ubiquitin-like modifier-dependent transcriptional repression of Smad4. J Biol Chem. 2005;280:10164-73 pubmed
    ..Here, we showed that Daxx interacts with Smad4 and represses its transcriptional activity via the C-terminal domain of Daxx...
  30. Wan M, Huang J, Jhala N, Tytler E, Yang L, Vickers S, et al. SCF(beta-TrCP1) controls Smad4 protein stability in pancreatic cancer cells. Am J Pathol. 2005;166:1379-92 pubmed
    Smad4, also known as deleted in pancreatic carcinoma locus 4 (DPC4), is a critical co-factor in signal transduction pathways activated by transforming growth factor (TGF)-beta-related ligands that regulate cell growth and differentiation...
  31. Zhao S, Venkatasubbarao K, Lazor J, Sperry J, Jin C, Cao L, et al. Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res. 2008;68:4221-8 pubmed publisher
    The role of Smad4 in transforming growth factor beta (TGFbeta)-mediated epithelial-mesenchymal transition (EMT), invasion, and metastasis was investigated using isogenically matched pancreatic cancer cell lines that differed only in ..
  32. Liffers S, Maghnouj A, Munding J, Jackstadt R, Herbrand U, Schulenborg T, et al. Keratin 23, a novel DPC4/Smad4 target gene which binds 14-3-3?. BMC Cancer. 2011;11:137 pubmed publisher
    Inactivating mutations of SMAD4 are frequent in metastatic colorectal carcinomas...
  33. Shin S, Kim S, Hong S, Kim Y, Song K, Park K, et al. Genetic alterations of K-ras, p53, c-erbB-2, and DPC4 in pancreatic ductal adenocarcinoma and their correlation with patient survival. Pancreas. 2013;42:216-22 pubmed publisher
    ..this study was to evaluate genetic alterations of K-ras, p53, c-erbB-2, and deleted in pancreatic cancer, locus 4 (DPC4) genes in pancreatic ductal adenocarcinoma and correlate these changes with patients' overall survival...
  34. Bachet J, Marechal R, Demetter P, Bonnetain F, Couvelard A, Svrcek M, et al. Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma. Ann Oncol. 2012;23:2327-35 pubmed publisher
    ..Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-? receptor, CXCR4, and LKB1...
  35. Gao S, Alarcon C, Sapkota G, Rahman S, Chen P, Goerner N, et al. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling. Mol Cell. 2009;36:457-68 pubmed publisher
    ..Previously identified as a regulator of renal sodium channels, Nedd4L is shown here to play a broader role as a general modulator of Smad turnover during TGF-beta signal transduction. ..
  36. Ali N, McKay M, Molloy M. Proteomics of Smad4 regulated transforming growth factor-beta signalling in colon cancer cells. Mol Biosyst. 2010;6:2332-8 pubmed publisher
    TGF-? signalling can play a paradoxical cell type specific role in cancer progression. Smad4 is a key mediator of the TGF-? pathway, and is mutated and/or deleted in many cancers...
  37. Shen W, Tao G, Li D, Zhu X, Bai X, Cai B. Inhibition of pancreatic carcinoma cell growth in vitro by DPC4 gene transfection. World J Gastroenterol. 2008;14:6254-60 pubmed
    To detect the expression of DPC4 in malignant and non-malignant specimens of human pancreas, and observe the inhibition of retroviral pLXSN containing DPC4 on pancreatic carcinoma cells in vitro...
  38. Morén A, Hellman U, Inada Y, Imamura T, Heldin C, Moustakas A. Differential ubiquitination defines the functional status of the tumor suppressor Smad4. J Biol Chem. 2003;278:33571-82 pubmed
    b>Smad4 is an essential signal transducer of all transforming growth factor-beta (TGF-beta) superfamily pathways that regulate cell growth and differentiation, and it becomes inactivated in human cancers...
  39. Iacobuzio Donahue C, Song J, Parmiagiani G, Yeo C, Hruban R, Kern S. Missense mutations of MADH4: characterization of the mutational hot spot and functional consequences in human tumors. Clin Cancer Res. 2004;10:1597-604 pubmed
    The mutational spectrum of MADH4 (DPC4/SMAD4) opens valuable insights into the functions of this protein that confer its tumor-suppressive nature in human tumors...
  40. Kim Y, Lee H, Lee H, Hur K, Kim W, Bang Y, et al. Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas. Ann Oncol. 2004;15:574-80 pubmed
    ..between clinicopathologic profiles and the patient's survival, the expression of common mediator Smad (Smad4) and inhibitory Smad (Smad7) were evaluated immunohistochemically in 304 consecutive gastric carcinomas using the ..
  41. Dupont S, Zacchigna L, Cordenonsi M, Soligo S, Adorno M, Rugge M, et al. Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell. 2005;121:87-99 pubmed
    ..Ecto is a RING-type ubiquitin ligase for Smad4, a TGF-beta signal transducer...
  42. Lazzereschi D, Nardi F, Turco A, Ottini L, D Amico C, Mariani Costantini R, et al. A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours. Oncogene. 2005;24:5344-54 pubmed
    ..We analysed 56 thyroid tumours of various histotypes for Smad4 mutations by PCR-SSCP and sequencing, linking them to Smad4 reactivity as examined by immunohistochemistry (IHC), ..
  43. Zhao S, Ammanamanchi S, Brattain M, Cao L, Thangasamy A, Wang J, et al. Smad4-dependent TGF-beta signaling suppresses RON receptor tyrosine kinase-dependent motility and invasion of pancreatic cancer cells. J Biol Chem. 2008;283:11293-301 pubmed publisher
    ..However, Smad signaling is altered by allelic deletion or intragenic mutation of the Smad4 gene in more than half of pancreatic ductal adenocarcinomas...
  44. 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...
  45. Lin X, Liang M, Liang Y, Brunicardi F, Feng X. SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4. J Biol Chem. 2003;278:31043-8 pubmed
    Tumor suppressor Smad4/DPC4 is a central intracellular signal transducer for transforming growth factor-beta (TGF-beta) signaling...
  46. 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...
  47. 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 (endoglin) or ACVRL1 (..
  48. Dubrovska A, Kanamoto T, Lomnytska M, Heldin C, Volodko N, Souchelnytskyi S. TGFbeta1/Smad3 counteracts BRCA1-dependent repair of DNA damage. Oncogene. 2005;24:2289-97 pubmed
    ..Thus, TGFbeta1/Smad3 suppresses BRCA1-dependent DNA repair in response to a DNA damaging agent. ..
  49. Ando T, Sugai T, Habano W, Jiao Y, Suzuki K. Analysis of SMAD4/DPC4 gene alterations in multiploid colorectal carcinomas. J Gastroenterol. 2005;40:708-15 pubmed
    Although recent animal studies have shown that SMAD4/DPC4 gene alterations are essential for late-stage intestinal tumorigenesis, the role of SMAD4/DPC4 gene alterations in primary human colorectal carcinomas is not fully understood...
  50. Kalo E, Buganim Y, Shapira K, Besserglick H, Goldfinger N, Weisz L, et al. Mutant p53 attenuates the SMAD-dependent transforming growth factor beta1 (TGF-beta1) signaling pathway by repressing the expression of TGF-beta receptor type II. Mol Cell Biol. 2007;27:8228-42 pubmed
    ..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...
  51. 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 ..
  52. van Hattem W, Brosens L, de Leng W, Morsink F, Lens S, Carvalho R, et al. Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut. 2008;57:623-7 pubmed publisher
    ..This syndrome is caused by germline mutation of either SMAD4 or BMPR1A, and possibly ENG...
  53. Chiba S, Takeshita K, Imai Y, Kumano K, Kurokawa M, Masuda S, et al. Homeoprotein DLX-1 interacts with Smad4 and blocks a signaling pathway from activin A in hematopoietic cells. Proc Natl Acad Sci U S A. 2003;100:15577-82 pubmed
    ..these cytokines bind to their respective receptor, a regulatory Smad is phosphorylated and becomes associated with Smad4, the common Smad, and the resulting complex translocates to the nucleus to regulate transcription...
  54. Long J, Wang G, Matsuura I, He D, Liu F. Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3). Proc Natl Acad Sci U S A. 2004;101:99-104 pubmed
    ..Taken together, our studies indicate that on TGF-beta treatment, PIAS3 can form a complex with Smads and p300/CBP and activate Smad transcriptional activity. ..
  55. Lampropoulos P, Zizi Sermpetzoglou A, Rizos S, Kostakis A, Nikiteas N, Papavassiliou A. Prognostic significance of transforming growth factor beta (TGF-?) signaling axis molecules and E-cadherin in colorectal cancer. Tumour Biol. 2012;33:1005-14 pubmed publisher
    ..aim of the present study was to evaluate TGF-?, TGF-? type I receptor (TGF-?R1), TGF-? type II receptor (TGF-?R2), Smad4, pSmad2/3, and E-cadherin expression in colorectal carcinoma and to correlate the obtained data with other ..
  56. Liang M, Melchior F, Feng X, Lin X. Regulation of Smad4 sumoylation and transforming growth factor-beta signaling by protein inhibitor of activated STAT1. J Biol Chem. 2004;279:22857-65 pubmed
    The tumor suppressor, Smad4/DPC4, is a common signal transducer in transforming growth factor-beta (TGF-beta) signaling...
  57. Zapatka M, Zboralski D, Radacz Y, Bockmann M, Arnold C, Schöneck A, et al. Basement membrane component laminin-5 is a target of the tumor suppressor Smad4. Oncogene. 2007;26:1417-27 pubmed
    The tumor suppressor Smad4 is involved in carcinogenesis mainly of the pancreas and colon...
  58. Blackford A, Serrano O, Wolfgang C, Parmigiani G, Jones S, Zhang X, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15:4674-9 pubmed publisher
    ..When adjusted for age, lymph node status, margin status, and tumor size, SMAD4 gene inactivation was significantly associated with shorter overall survival (hazard ratio, 1...
  59. 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 ..
  60. 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...
  61. Kang Y, He W, Tulley S, Gupta G, Serganova I, Chen C, et al. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci U S A. 2005;102:13909-14 pubmed
    ..Genetic depletion experiments further demonstrate that Smad4 contributes to the formation of osteolytic bone metastases and is essential for the induction of IL-11, a gene ..
  62. Won K, Kim Y, Park Y. Expression of Smad and its signalling cascade in osteosarcoma. Pathology. 2010;42:242-7 pubmed publisher
    ..We assessed the immunohistochemical expression profiles of Smad2, P-Smad2, Smad4, and p21/WAF1 proteins in 34 cases of osteosarcoma...
  63. Morén A, Imamura T, Miyazono K, Heldin C, Moustakas A. Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. J Biol Chem. 2005;280:22115-23 pubmed
    b>Smad4 mediates signaling by the transforming growth factor-beta (TGF-beta) superfamily of cytokines. Smad signaling is negatively regulated by inhibitory (I) Smads and ubiquitin-mediated processes...
  64. D Inzeo S, Nicolussi A, Donini C, Zani M, Mancini P, Nardi F, et al. A novel human Smad4 mutation is involved in papillary thyroid carcinoma progression. Endocr Relat Cancer. 2012;19:39-55 pubmed publisher
    ..b>Smad4 plays an important role in human physiology, and its mutations were found with high frequency in wide range of ..
  65. Aretz S, Stienen D, Uhlhaas S, Stolte M, Entius M, Loff S, et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007;44:702-9 pubmed
    In patients with juvenile polyposis syndrome (JPS) the frequency of large genomic deletions in the SMAD4 and BMPR1A genes was unknown.
  66. Calva Cerqueira D, Chinnathambi S, Pechman B, Bair J, Larsen Haidle J, Howe J. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet. 2009;75:79-85 pubmed publisher
    ..Germline point mutations in SMAD4 and BMPR1A have been identified as causing JPS in approximately 40-60% of patients, but few studies have looked at ..
  67. Hao J, Zhang S, Zhou Y, Hu X, Shao C. MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer. FEBS Lett. 2011;585:207-13 pubmed publisher
    ..Furthermore, DPC4/Smad4 is identified as a target of miR-483-3p and their expression levels are inversely correlated in human clinical ..
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