vendredi 27 avril 2012

Mutated genes in cancer (67) – SMAD4


In databases:

● Entrez ( 4089 or SMAD4
● Ensembl ( ENSG00000141646
● UniProt ( Q13485
● GeneCards ( SMAD4
● HGNC ( 6770 or SMAD4

Gene locus:


Protein name:

SMAD family member 4

Protein Size:

552 amino acids; about 60 kDa


SMAD4 encodes a member of the Smad family of signal transduction proteins. Smad4 acts as an intracellular mediator of TGF-β family and activin type 1 receptor, to regulate cell growth and differentiation.

Cancer-related alterations:

Somatic mutations in SMAD4 appear frequent in pancreatic, colorectal, upper aerodigestive tract, thyroid, biliary tract cancers. About one half of these mutations are substitutions. No specific mutation hot spot has been identified. Mutant Smad4 proteins, identified in human carcinomas, were found to be impaired in their ability to regulate gene transcription.

Germline alterations of SMAD4 are a cause of juvenile polyposis syndrome (JPS or JP). JPS is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. Defects in SMAD4 may also be observed in some patients with juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT), in which JP and hereditary hemorrhagic telangiectasia (HHT) coexist in a single individual. Both JIP and HHT are autosomal dominant disorders, but with distinct and non-overlapping clinical features. HHT is a vascular malformation disorder.

References (open access):

Juvenile Polyposis Syndrome. Larsen Haidle J, Howe JR. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. SourceGeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.2003 May 13 [updated 2008 Sep 09].

Smad4-mediated TGF-beta signaling in tumorigenesis. Yang G, Yang X. Int J Biol Sci. 2010 Jan 1;6(1):1-8.

SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Cameron JL, Olino K, Schulick R, Winter J, Herman JM, Laheru D, Klein AP, Vogelstein B, Kinzler KW, Velculescu VE, Hruban RH. Clin Cancer Res. 2009 Jul 15;15(14):4674-9.

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