SMAD4 (mothers against decapentaplegic homolog 4 (Drosophila))
| Written | 2004-08 | Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire |
| Service de Biochimie et Biologie moleculaire, Hopital Paul Brousse, Faculte de Medecine Paris Sud, 94 800 Villejuif, France |
(Note : for Links provided by Atlas : click)
1. Identity
| Alias_names | General Information |
| MAD, mothers against decapentaplegic homolog 4 (Drosophila) | |
| SMAD, mothers against DPP homolog 4 (Drosophila) | |
| Alias_symbol (synonym) | DPC4 |
| Other alias | JIP |
| HGNC (Hugo) | SMAD4 |
| LocusID (NCBI) | 4089 |
| Atlas_Id | 371 |
| Location | 18q21.2 [Link to chromosome band 18q21] |
| Location_base_pair | Starts at 51030213 and ends at 51085041 bp from pter ( according to hg19-Feb_2009) [Mapping SMAD4.png] |
 | |
| Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics | |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| COBLL1 (2q24.3) / SMAD4 (18q21.2) | DACH1 (13q21.33) / SMAD4 (18q21.2) | ELAC1 (18q21.2) / SMAD4 (18q21.2) | |
| PCSK2 (20p12.1) / SMAD4 (18q21.2) | SMAD4 (18q21.2) / RAX (18q21.32) | SMAD4 (18q21.2) / SMAD4 (18q21.2) | |
2. DNA/RNA
| Description | The gene encompasses 49.5 kb of DNA; 13 exons. |
| Transcription | 3220 nucleotides mRNA. |
3. Protein
| Description | 552 amino acids; 60.4 kDa protein. Smad4 belongs to the Darfwin family of proteins which harbours two conserved amino- and carboxyl-terminal domains known as MH1 and MH2, respectively. Smad4 in the basal state is found mostly as a homo-oligomer, most likely a trimer. |
| Expression | Ubiquitous. |
| Function | Smad4 is an intracellular mediator of TGF-beta family and activin type 1 receptor. Smad4 mediate TGF-beta signaling to regulate cell growth and differentiation. TGF-beta stimulation leads to phosphorylation and activation of Smad2 and Smad3, which form complexes with Smad4 that accumulate in the nucleus and regulate transcription of target genes. By interacting with DNA-binding proteins, Smad complexes then positively or negatively regulate the transcription of target genes. |
| Homology | With the other members of the Darfwin/Smad family. |
4. Implicated in
| Note | |
| Entity | Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome |
| Disease | Juvenile polyposis and hereditary hemorrhagic telangiectasia syndrome is an autosomal dominant disorder with distinct clinical features. One form corresponding to a predisposition to gastrointestinal polyps and cancer may be associated with mutations in Smad4 gene. |
| Oncogenesis | Polyps are formed by inactivation of the Smad4 gene through germline mutations and loss of the unaffected wild-type allele. |
| Entity | Pancreatic carcinoma |
| Disease | 90% of pancreatic carcinomas show allelic loss at 18q. A consensus region of homozygous deletion at 18q21.1 was found in one third of pancreatic carcinomas and intragenic mutations were found in another 20% of this tumor type. |
| Prognosis | Smad4 expression may be a molecular prognostic marker for pancreatic carcinoma. A lower patient survival may be associated with loss of Smad4 expression. |
| Oncogenesis | Smad4 was proposed to be a tumor suppressor gene that may function to disrupt TGF-beta signaling. Mutant Smad4 proteins, identified in human carcinomas, were found to be impaired in their ability to regulate gene transcription. Most of Smad4 gene mutations in human cancer are missense, nonsense, and frameshift mutations at the mad homology 2 region (MH2) which interfere with the homo-oligomer formation of Smad4 protein and hetero-oligomer formation between Smad4 and Smad2 proteins, resulting in disruption of TGF-beta signaling. |
5. To be noted
| Mutation of Smad4 is seen also in approximately 15% of colorectal carcinomas and occasionally (less than 10%) in the rest of human cancers such as breast, ovarian, hepatocellular or head and neck squamous cell carcinomas. |
6. Bibliography
| Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients. |
| Friedl W, Kruse R, Uhlhaas S, Stolte M, Schartmann B, Keller KM, Jungck M, Stern M, Loff S, Back W, Propping P, Jenne DE |
| Genes, chromosomes & cancer. 1999 ; 25 (4) : 403-406. |
| PMID 10398437 |
| Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. |
| Friedl W, Uhlhaas S, Schulmann K, Stolte M, Loff S, Back W, Mangold E, Stern M, Knaebel HP, Sutter C, Weber RG, Pistorius S, Burger B, Propping P |
| Human genetics. 2002 ; 111 (1) : 108-111. |
| PMID 12136244 |
| A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). |
| Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA |
| Lancet. 2004 ; 363 (9412) : 852-859. |
| PMID 15031030 |
| DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. |
| Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE |
| Science (New York, N.Y.). 1996 ; 271 (5247) : 350-353. |
| PMID 8553070 |
| Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases. |
| Houlston R, Bevan S, Williams A, Young J, Dunlop M, Rozen P, Eng C, Markie D, Woodford-Richens K, Rodriguez-Bigas MA, Leggett B, Neale K, Phillips R, Sheridan E, Hodgson S, Iwama T, Eccles D, Bodmer W, Tomlinson I |
| Human molecular genetics. 1998 ; 7 (12) : 1907-1912. |
| PMID 9811934 |
| A gene for familial juvenile polyposis maps to chromosome 18q21.1. |
| Howe JR, Ringold JC, Summers RW, Mitros FA, Nishimura DY, Stone EM |
| American journal of human genetics. 1998 ; 62 (5) : 1129-1136. |
| PMID 9545410 |
| Mutations in the SMAD4/DPC4 gene in juvenile polyposis. |
| Howe JR, Roth S, Ringold JC, Summers RW, Järvinen HJ, Sistonen P, Tomlinson IP, Houlston RS, Bevan S, Mitros FA, Stone EM, Aaltonen LA |
| Science (New York, N.Y.). 1998 ; 280 (5366) : 1086-1088. |
| PMID 9582123 |
| Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. |
| Inman GJ, Nicol´ FJ, Hill CS |
| Molecular cell. 2002 ; 10 (2) : 283-294. |
| PMID 12191474 |
| Distinct oligomeric states of SMAD proteins in the transforming growth factor-beta pathway. |
| Jayaraman L, Massague J |
| The Journal of biological chemistry. 2000 ; 275 (52) : 40710-40717. |
| PMID 11018029 |
| DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck squamous cell carcinoma. |
| Kim SK, Fan Y, Papadimitrakopoulou V, Clayman G, Hittelman WN, Hong WK, Lotan R, Mao L |
| Cancer research. 1996 ; 56 (11) : 2519-2521. |
| PMID 8653689 |
| Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. |
| Miyaki M, Iijima T, Konishi M, Sakai K, Ishii A, Yasuno M, Hishima T, Koike M, Shitara N, Iwama T, Utsunomiya J, Kuroki T, Mori T |
| Oncogene. 1999 ; 18 (20) : 3098-3103. |
| PMID 10340381 |
| Role of Smad4 (DPC4) inactivation in human cancer. |
| Miyaki M, Kuroki T |
| Biochemical and biophysical research communications. 2003 ; 306 (4) : 799-804. |
| PMID 12821112 |
| DPC4 gene in various tumor types. |
| Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero RA Jr, Meltzer PS, Hahn SA, Kern SE |
| Cancer research. 1996 ; 56 (11) : 2527-2530. |
| PMID 8653691 |
| Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator. |
| Shioda T, Lechleider RJ, Dunwoodie SL, Li H, Yahata T, de Caestecker MP, Fenner MH, Roberts AB, Isselbacher KJ |
| Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (17) : 9785-9790. |
| PMID 9707553 |
| Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. |
| Thiagalingam S, Lengauer C, Leach FS, Schutte M, Hahn SA, Overhauser J, Willson JK, Markowitz S, Hamilton SR, Kern SE, Kinzler KW, Vogelstein B |
| Nature genetics. 1996 ; 13 (3) : 343-346. |
| PMID 8673134 |
| Smad2 and Smad4 gene mutations in hepatocellular carcinoma. |
| Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M |
| Oncogene. 1999 ; 18 (34) : 4879-4883. |
| PMID 10490821 |
| Human Smad3 and Smad4 are sequence-specific transcription activators. |
| Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B, Kern SE |
| Molecular cell. 1998 ; 1 (4) : 611-617. |
| PMID 9660945 |
| Targeted deletion of Smad4 shows it is required for transforming growth factor beta and activin signaling in colorectal cancer cells. |
| Zhou S, Buckhaults P, Zawel L, Bunz F, Riggins G, Dai JL, Kern SE, Kinzler KW, Vogelstein B |
| Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (5) : 2412-2416. |
| PMID 9482899 |
7. Citation
| This paper should be referenced as such : |
| Saffroy, R ; Lemoine, A ; Debuire, B |
| SMAD4 (mothers against decapentaplegic homolog 4 (Drosophila)) |
| Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):287-288. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/SMAD4ID371.html |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 5 ] |
|
Colon: Colorectal adenocarcinoma
Liver: Hepatocellular carcinoma Pancreatic tumors: an overview ELAC1/SMAD4 (18q21) SMAD4/RAX (18q21) |
| Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ] |
| Familial Juvenile Polyposis Syndrome |
8. External links
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Thu Jan 17 19:08:36 CET 2019 |
For comments and suggestions or contributions, please contact us atlasgeneticsoncology@usal.es.