OMIM :  600993

GENECARD : MADH4

CGAP : 75862

SYNONYMS

• SMAD4

• DPC4

• MAD (mothers against decapentaplegic, Drosophila) homolog 4

Chromosome human

• DPC4 is a tumor-suppressor gene on chromosome 18q21.1.McCarthy DM, Brat DJ, Wilentz RE, Yeo CJ, Cameron JL, Kern SE, Hruban RH.

Clinical

• Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entity. Sohn TA, Yeo CJ, Cameron JL, Iacobuzio-Donahue CA, Hruban RH, Lillemoe KD.

• Biliopancreatic malignancy: screening the at risk patient with molecular markers. Caldas C.

Complimentation      

• Apart from the functional loss of DPC4 due to mutations or homozygous deletion, a lack of the TGF-beta receptors, particularly RII and RIII, may contribute to a loss of TGF-beta signaling in a population of pancreatic cancers. Venkatasubbarao K, Ahmed MM, Mohiuddin M, Swiderski C, Lee E, Gower WR Jr, Salhab KF, McGrath P, Strodel W, Freeman JW.

DNA Structure

• The 18q21 region in colorectal and pancreatic cancer: independent loss of DCC and DPC4 expression. Barbera VM, Martin M, Marinoso L, Munne A, Carrato A, Real FX, Fabre M. 

• 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.

Function

• Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors. Bartsch D, Hahn SA, Danichevski KD, Ramaswamy A, Bastian D, Galehdari H, Barth P, Schmiegel W, Simon B, Rothmund M.

• Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis.Schwarte-Waldhoff I, Volpert OV, Bouck NP, Sipos B, Hahn SA, Klein-Scory S, Luttges J, Kloppel G, Graeven U, Eilert-Micus C, Hintelmann A, Schmiegel W.

• TIEG proteins join the Smads as TGF-beta-regulated transcription factors that control pancreatic cell growth. Cook T, Urrutia R.

• Dpc4 protein in mucinous cystic neoplasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Iacobuzio-Donahue CA, Wilentz RE, Argani P, Yeo CJ, Cameron JL, Kern SE, Hruban RH.

Gene Frequencey (tumor)

• Loss of heterozygosity (LOH) of at the DPC4(18q21.1) locus is observed in 15 of 25 tumors(60%). Heinmoller E, Dietmaier W, Zirngibl H, Heinmoller P, Scaringe W, Jauch KW, Hofstadter F, Ruschoff J.

Phenotype       

• The protein products of these gene mutations are potential tumor antigens, thus genotype expression can be detected by phenotype. Chu TM.

Regulation

• TIEG proteins join the Smads as TGF-beta-regulated transcription factors that control pancreatic cell growth. Cook T, Urrutia R.

• Overexpression of Smad2 and colocalization with TGF-beta1 in human pancreatic cancer. Kleeff J, Friess H, Simon P, Susmallian S, Buchler P, Zimmermann A, Buchler MW, Korc M.

• The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Kleeff J, Ishiwata T, Maruyama H, Friess H, Truong P, Buchler MW, Falb D, Korc M.

RNA structure

• The amino acid sequence encoded by exon 8 of the human iPLA2 gene is proline-rich and shares a consensus motif of PX5PX8HHPX12NX4Q with the proline-rich middle linker domains of the Smad proteins DAF-3 and Smad4.  Ma Z, Wang X, Nowatzke W, Ramanadham S, Turk J.

Signaling Pathway

• Overexpression of Smad2 and colocalization with TGF-beta1 in human pancreatic cancer. Kleeff J, Friess H, Simon P, Susmallian S, Buchler P, Zimmermann A, Buchler MW, Korc M.

• Transforming growth factor-beta responsiveness in DPC4/SMAD4-null cancer cells. Dai JL, Schutte M, Bansal RK, Wilentz RE, Sugar AY, Kern SE.

 Tumor gene type          

• DPC4 is a tumor-suppressor gene on chromosome 18q21.1. McCarthy DM, Brat DJ, Wilentz RE, Yeo CJ, Cameron JL, Kern SE, Hruban RH.

Tumor incidence

• Dpc4 expression was seen in 28 (97%) of the associated 29 invasive cancers. Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, Wilentz RE, Argani P, Sohn TA, Yeo CJ, Cameron JL, Kern SE, Hruban RH.

Tumor type      

• The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Luttges J, Zamboni G, Longnecker D, Kloppel G.