The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cancer, is a central mediator of TGF-b signaling. It was previously shown that mice homozygous for a null mutation of Smad4 (Smad4 7/7 ) died prior to gastrulation displaying impaired extraembryonic membrane formation and endoderm dierentiation. Here we show that Smad4 +/7 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 ®nally 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 haploinsuciency of Smad4 is sucient for tumor initiation. Our data also showed that overexpression of TGF-b1 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.

Transforming growth factors-beta (TGF-beta) are 25 kilodalton (kDa) homodimeric peptides with multifunctional actions controlling the growth, differentiation and function of a broad range of target cells of both epithelial and mesenchymal derivation. They are expressed early in embryogenesis and their tissue-specific and developmentally dependent expression is strongly suggestive of an essential role in particular morphogenetic and histogenetic events. Five distinct TGF-beta s have been characterized so far, with 65-80% homology to each other. By using both molecular biological and immunohistochemical techniques, we are currently attempting to define specific sites of expression of the different TGF-beta s and to determine whether TGF-beta s 1-5 might have unique functions in development and in the mature organism. Comparative study of the promoter regions for the different TGF-beta s and for any particular TGF-beta in different species is also underway. Mechanistically, TGF-beta s act to control gene expression of their target cells, many of their actions converging on a complex, multifaceted scheme of control of matrix proteins and their interactions with cells; these effects on matrix are thought to mediate many of the effects of TGF-beta on development.

Objective. Interleukin-1 (IL-1) and transforming growth factor ␤1 (TGF␤1) play major roles in osteoarticular diseases, exerting opposite effects on both the catabolism and anabolism of cartilage matrix. Previous findings suggest that IL-1 and TGF␤1 could function in a feedback interaction. However, the effect exerted by IL-1 on expression of TGF␤ by articular chondrocytes is, so far, poorly understood. The present study was carried out to determine the influence of IL-1␤ on the expression of TGF␤1 by bovine articular chondrocytes (BACs) in primary culture.Methods. BAC primary cultures were treated with IL-1␤, and TGF␤1 messenger RNA (mRNA) steadystate levels and protein expression were measured by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Transient transfection of TGF␤1 gene promoter constructs was performed to delineate the DNA sequences that mediate the IL-1␤ effect. Electrophoretic mobility shift assays (EMSAs) and supershift analysis were used to characterize the transcription factors binding to these sequences. Results. Cultured BACs responded to IL-1␤ ex-

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