The multifunctional actions of transforming growth factor beta 1 (TGF-beta 1) indicate that it has a pivotal control function in many physiological and pathological processes. An important property of TGF-beta 1 is its ability to activate its own mRNA expression and thereby increase its own secretion. Two distinct regions of the promoter of the TGF-beta 1 gene are responsive to autoregulation: one 5' to the upstream transcriptional start site and another located between the two major start sites. In both promoter regions, autoinduction is mediated by binding of the AP-1 (Jun-Fos) complex. An important contribution to this positive regulation is the autoactivation of c-jun transcription by AP-1. Cotransfection of antisense c-jun or antisense c-fos expression vectors prevents TGF-beta 1 autoinduction. These results demonstrate that both components of the AP-1 complex are required for TGF-beta 1 autoinduction. Induction of jun expression by TGF-beta 1, as well as jun autoinduction, may amplify the action of TGF-beta 1 during normal development and oncogenesis.

Aberrant promoter methylation and the associated loss of gene expression is a common accompaniment of human cancers. Nonetheless, it has been challenging to demonstrate in any given tumour that methylation of a specific gene was causal and not consequent to malignant transformation. In this regard, our attention was drawn to the genesis of gastric cancers in individuals with hereditary diffuse gastric cancer (HDGC). These individuals harbour germline mutations in the gene encoding E-cadherin, CDH1, but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. These findings suggested the hypothesis that CDH1 promoter methylation might function as the 'second genetic hit' in the genesis of these cancers.

We have found several genetic changes in the 8 (13,14). In another report, reduced levels of the TGF-P type I receptor were found in 82% of human gastric cancer tissues as determined by cross-linking (15). One TGF-f3-sensitive gastric cancer cell line expressed only the type I receptor, while a TGF-3-resistant cell line had all three types of TGF-P receptors, and it was suggested the type I receptor might be linked to growth inhibition by TGF-f3 (15,16). In contrast, in a cell fusion system, the type II receptor appeared necessary for mediating the effects of TGF-,B on inhibition of growth but not on activation of certain target genes (17,18).In the present study, we examined the growth inhibitory activity of TGF-p in eight human gastric cancer cell lines and the correlation between responsiveness to TGF-f3 and the genetic changes and expression patterns ofthe TGF-j3 type II receptor gene. The ability of TGF-13 to induce mRNA for plasminogen activator inhibitor type 1 (PAl-i) was also investigated as an indicator of the effects of TGF-p on target gene expression. The results indicate that genetic changes in the TGF-3 type II receptor gene occur commonly in gastric cancer cells resistant to the growth inhibitory action of TGF-P. We also show several aberrant expression patterns of type II receptor mRNA in the TGF-(3-resistant cells and corresponding changes in the expression of TGF-13 type II receptor at the protein level, both of which showed a good correlation with the sensitivity of these cells to growth inhibition by TGF-P. MATERIALS AND METHODSCell Lines and Cell Culture. Cell lines were established from gastric carcinomas of individual patients (primary tumors or malignant ascites), either directly or after heterotransplantation in athymic nude mice and

Tigers and their close relatives (Panthera) are some of the world’s most endangered species. Here we report the de novo assembly of an Amur tiger whole-genome sequence as well as the genomic sequences of a white Bengal tiger, African lion, white African lion and snow leopard. Through comparative genetic analyses of these genomes, we find genetic signatures that may reflect molecular adaptations consistent with the big cats’ hypercarnivorous diet and muscle strength. We report a snow leopard-specific genetic determinant in EGLN1 (Met39>Lys39), which is likely to be associated with adaptation to high altitude. We also detect a TYR260G>A mutation likely responsible for the white lion coat colour. Tiger and cat genomes show similar repeat composition and an appreciably conserved synteny. Genomic data from the five big cats provide an invaluable resource for resolving easily identifiable phenotypes evident in very close, but distinct, species.