7040

TGFB1

CED|DPD1|LAP|TGFB|TGFbeta;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

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.

Transforming growth factor-beta (TGF-beta) is a potent regulator of tissue homeostasis and can act as both a tumor suppressor and a tumor promoter. The ability to induce cell cycle arrest is a major component of the tumor suppressor function of TGF-beta. Lung, mammary, and skin epithelial cells exhibit a common minimal cytostatic program in response to TGF-beta signaling involving the repression of the growth-promoting factors c-MYC, Id1, Id2, and Id3. Loss of c-MYC expression is a pivotal event in this process, resulting in derepression of the cyclin-dependent kinase inhibitors CDKN1A (p21) and CDKN2B (p15) and ultimately leading to growth arrest. It is not clear, however, which responses are necessary for TGF-beta-mediated growth arrest in other cell types. Here, in human Burkitt lymphoma cells transformed by deregulated c-MYC expression, we demonstrate that efficient TGF-beta-induced cytostasis can occur despite both maintenance of c-MYC levels and a lack of p21 and p15 induction. TGF-beta treatment also results in induction, rather than repression, of Id1 and Id2 expression. In this context, growth arrest correlates with transcriptional repression of E2F-1, and overexpression of E2F-1 in Burkitt lymphoma cells largely overcomes the TGF-beta-mediated G(1) arrest phenotype. These data indicate that deregulation of c-MYC in lymphoma cells does not overcome the tumor suppressor function of TGF-beta and that repression of E2F-1 transcription is sufficient for the efficient induction of cytostasis.

Components of the transforming growth factor-beta (TGF-beta) signal pathway function as classic tumor suppressors, but the role of the TGF-betas themselves is less clear. Here we show that mice heterozygous for deletion of the TGF-beta1 gene express only 10-30% of wild-type TGF-beta1 protein levels. Although grossly normal, these mice have a subtly altered proliferative phenotype, with increased cell turnover in the liver and lung. Treatment of these mice with chemical carcinogens resulted in enhanced tumorigenesis when compared with wild-type littermates. However, tumors in the heterozygous mice did not lose the remaining wild-type TGF-beta1 allele, indicating that the TGF-beta1 ligand is a new form of tumor suppressor that shows true haploid insufficiency in its ability to protect against tumorigenesis.