Oncogene database

7040

TGFB1

transforming growth factor, beta 1;TGFB1;transforming growth factor, beta 1

TGF-beta-1|latency-associated peptide|prepro-transforming growth factor beta-1|transforming growth factor beta-1

19q13.1

protein-coding

Transforming growth factor beta (TGFbeta) plays a dual role in oncogenesis, acting as both a tumor suppressor and a tumor promoter. These disparate processes of suppression and promotion are mediated primarily by Smad and non-Smad signaling, respectively. A central issue in understanding the role of TGFbeta in the progression of epithelial cancers is the elucidation of the mechanisms underlying activation of non-Smad signaling cascades. Because the potent lipid mediator sphingosine-1-phosphate (S1P) has been shown to transactivate the TGFbeta receptor and activate Smad3, we examined its role in TGFbeta activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and promotion of migration and invasion of esophageal cancer cells. Both S1P and TGFbeta activate ERK1/2, but only TGFbeta activates Smad3. Both ligands promoted ERK1/2-dependent migration and invasion. Furthermore, TGFbeta rapidly increased S1P, which was required for TGFbeta-induced ERK1/2 activation, as well as migration and invasion, since downregulation of sphingosine kinases, the enzymes that produce S1P, inhibited these responses. Finally, our data demonstrate that TGFbeta activation of ERK1/2, as well as induction of migration and invasion, is mediated at least in part by ligation of the S1P receptor, S1PR2. Thus, these studies provide the first evidence that TGFbeta activation of sphingosine kinases and formation of S1P contribute to non-Smad signaling and could be important for progression of esophageal cancer.

Interactions between TGFbeta1 and ras signaling pathways play an important role in cancer development. Here we show that in primary mouse keratinocytes, v-ras(Ha) does not block the early biochemical events of TGFbeta1 signal transduction but does alter global TGFbeta1 mediated gene expression in a gene specific manner. expression of Smad3 dependent TGFbeta1 early response genes and the TGFbeta1 cytostatic gene expression response were not altered by v-ras(Ha) consistent with an intact TGFbeta1 growth arrest. However, TGFbeta1 and v-ras(Ha) cause significant alteration in genes regulating matrix remodeling as the TGFbeta1 induction of extracellular matrix genes was blocked by v-ras(Ha) but specific matrix proteases associated with cancer progression were elevated. Smad3 deletion in keratinocytes repressed normal differentiation maker expression and caused expression of Keratin 8 a simple epithelial keratin and marker of malignant conversion. Smad3 was required for the TGFbeta1 cytostatic response in v-ras(Ha) keratinocytes, but also for protease induction, keratinocyte attachment and migration. These results show that pro-oncogenic activities of TGFbeta1 can occur early in carcinogenesis before loss of its tumor suppressive function and that selective regulation rather than complete inactivation of Smad3 function may be crucial for tumor progression.