Journal
ONCOGENE
Volume 19, Issue 15, Pages 1868-1874Publisher
STOCKTON PRESS
DOI: 10.1038/sj.onc.1203504
Keywords
Smad4; Dpc4; juvenile polyposis; gastric cancer; TGF beta 1; cyclin D1
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The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cancer, is a central mediator of TGF-P signaling. It was previously shown that mice homozygous for a null mutation of Smad4 (Smad4(-/-)) died prior to gastrulation displaying impaired extra-embryonic membrane formation and endoderm differentiation. Here we show that Smad4(+/-) mice began to develop polyposis in the fundus and antrum when they were over 6-12 months old, and in the duodenum and cecum in older animals at a lower frequency, With increasing age, polyps in the antrum show sequential changes from hyperplasia, to dysplasia, in-situ carcinoma, and finally invasion. These alterations are initiated by a dramatic expansion of the gastric epithelium where Smad4 is expressed. However, loss of the remaining Smad4 wild-type allele was detected only in later stages of tumor progression, suggesting that haploinsufficiency of Smad4 is sufficient for tumor initiation. Our data also showed that overexpression of TGF-beta 1 and Cyclin D1 was associated with increased proliferation of gastric polyps and tumors. These studies demonstrate that Smad4 functions as a tumor suppressor in the gastrointestinal tract and also provide a valuable model for screening factors that promote or prevent gastric tumorigenesis.
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