The tumor suppressor gene Smad4 (DPC4) at chromosome 18q21.1 belongs to the Smad family, which mediates the TGFbeta signaling pathway suppressing epithelial cell growth. (MIM. 600993)
MADH4 (SMAD4) encodes a component of the TGF-â growth-inhibitory signal transduction pathway. The tumor suppressor function of SMAD4 lies in its capacity to mediate the effects of transforming growth factor–â superfamily signaling.
It is inactivated in approximately 50% of pancreatic cancers, while mutations in SMAD2, another component of the pathway, are present in some colorectal tumors. Because of its association with pancreatic cancers, MADH4 (SMAD4) was originally designated DPC4, deleted in pancreatic cancer.
Pathology
germline mutations of MADH4 in familial juvenile polyposis
- polyps are formed by inactivation of the Smad4 gene through germline mutation and loss of the unaffected wild-type allele.
germline mutations of MADH4 in familial juvenile polyposis and hereditary haemorrhagic telangiectasia association (JP-HHT syndrome) (15031030)
inactivation by somatic mutations and somatic deletions in 55% of pancreatic carcinomas
somatic inactivation in colorectal carcinomas
- inactivation of the Smad4 gene through homozygous deletion or intragenic mutation occurs frequently in association with malignant progression)
- In primary colorectal tumors, loss of E-cadherin is highly correlated with loss of SMAD4.
- Furthermore, in small intestinal adenocarcinomas, inactivating mutations of the SMAD4 gene have been observed.
somaic mutation in other human cancers
- missense, nonsense, and frameshift mutations at the mad homology 2 region (MH2),
- interference with the homo-oligomer formation of Smad4 protein and the hetero-oligomer formation between Smad4 and Smad2 proteins, resulting in disruption of TGFbeta signaling.
See also:
TGF-beta signaling pathway (TGF-beta signaling)
MADHs (SMADs): MADH1, MADH2, MADH3, MADH4
References
Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004 Mar 13;363(9412):852-9. PMID: 15031030
Miyaki M, Kuroki T. Role of Smad4 (DPC4) inactivation in human cancer. Biochem Biophys Res Commun. 2003 Jul 11;306(4):799-804. PMID: 12821112