Deep-water archaeological discoveries on Eratosthenes Seamount

Nature Cell Biology, 2009

Epithelial-mesenchymal transition (EMT) is essential for organogenesis and is triggered during carcinoma progression to an invasive state. Transforming growth factor-beta (TGF-beta) cooperates with signalling pathways, such as Ras and Wnt, to induce EMT, but the molecular mechanisms are not clear. Here, we report that SMAD3 and SMAD4 interact and form a complex with SNAIL1, a transcriptional repressor and promoter of EMT. The SNAIL1-SMAD3/4 complex was targeted to the gene promoters of CAR, a tight-junction protein, and E-cadherin during TGF-beta-driven EMT in breast epithelial cells. SNAIL1 and SMAD3/4 acted as co-repressors of CAR, occludin, claudin-3 and E-cadherin promoters in transfected cells. Conversely, co-silencing of SNAIL1 and SMAD4 by siRNA inhibited repression of CAR and occludin during EMT. Moreover, loss of CAR and E-cadherin correlated with nuclear co-expression of SNAIL1 and SMAD3/4 in a mouse model of breast carcinoma and at the invasive fronts of human breast canc...

PROTEOMICS, 2004

Transforming growth factor-b (TGFb) is a potent regulator of angiogenesis affecting proliferation, differentiation and migration of endothelial cells. The effect of TGFb on endothelial cells depends on the origin of the cells and on the experimental conditions. Global analysis of TGFb signalling is expected to unveil mechanisms of this variability and identify novel targets of the growth factor. Here, we report proteome profiling of human microvascular endothelial cells obtained from dermis, which were treated with TGFb1 and compared to nontreated cells. We identified 54 proteins affected by TGFb1 using two-dimensional gel electrophoresis and peptide mass fingerprinting. Thirteen of the identified proteins are involved in various signalling processes. Seven proteins are involved in cytoskeleton rearrangements and six are involved in regulation of metabolism. Ten proteins were identical to predicted hypothetical proteins with no assigned functions. In agreement with the effect of TGFb1 on components of the cytoskeleton, TGFb1 induces actin cytoskeleton rearrangements. TGFb1 also affected expression of E2F6, p57Kip2, G(q)a, hnRNP A1 and myosin light chain proteins as shown by immunoblotting. Down-regulation of the transcriptional repressor E2F6 by TGFb1 correlated with a weak growth-inhibitory activity of TGFb1 on HMVEC-d cells. Twenty-five of the identified proteins have not previously been described as being regulated by TGFb1, providing new insights into TGFb1 signalling in endothelial cells.

Oncogenesis, 2018

Carcinomas, such as colon cancer, initiate their invasion by rescuing the innate plasticity of both epithelial cells and stromal cells. Although Snail is a transcriptional factor involved in the Epithelial-Mesenchymal Transition, in recent years, many studies have also identified the major role of Snail in the activation of Cancer-Associated Fibroblast (CAF) cells and the remodeling of the extracellular matrix. In CAFs, Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant. High expression of both SNAI1 and PDGF receptors is associated with poor prognosis in cancer patients, but the mechanism(s) that underlie these connections are not understood. In this study, we demonstrate that PDGF-activated fibroblasts stimulate extracellular matrix (ECM) fiber remodeling and deposition. Furthermore, we describe how SNAI1, through the FAK pathway, is a necessary factor for ECM fiber organization. The parallel-oriented fibers are used by endothelial cells as ...

Developmental Dynamics, 2012

Pathology oncology research : POR, 2013

Transforming growth factor β (TGF-β) superfamily consists of numerous cytokins that regulate various cellular processes. TGF-β, the prototype of the family, signals through its cell surface serine/threonin kinase receptors and besides its role in cell differentiation, migration, adhesion etc. it is also able to induce epithelial-mesenchymal (EMT) transition via both Smad- pathway and MAPK- pathway. Among the different types of epithelial-mesenchymal transition, type II that is described to be associated with wound healing, tissue regeneration, organ fibrosis and is induced upon inflammatory stimuli. It can be triggered by secretion of growth factors such as TGF-β, EGF. Different endocytic routes are used for the internalization of TGF-β ligand and its receptors and these pathways can control the activity of downstream events. Internalization via clathrin-coated vesicles promotes the signaling while the caveola-mediated endocytosis plays important role in the termination of the event...

Cardiovascular Research, 2010

Time for primary review: 29 days Aims Endothelial progenitor cells (EPC) have been shown to repair pulmonary endothelium, although they can also migrate into the arterial intima and differentiate into smooth muscle-like (mesenchymal) cells contributing to intimal hyperplasia. The molecular mechanisms by which this process proceeds have not been fully elucidated. Here, we study whether genes involved in the endothelial-to-mesenchymal transition (EnMT) may contribute to the mesenchymal phenotype acquisition of EPC and we evaluate whether transforming growth factor b1 (TGFb1) is involved in this process. Methods and results Our results show that co-culture of EPC with smooth muscle cells (SMC) increases the expression of the mesenchymal cell markers a-smooth muscle actin, sm22-a, and myocardin, and decreases the expression of the endothelial cell marker CD31. In the same conditions, we also observed a concomitant increase in the gene expression of the EnMT-related transcription factors: slug, snail, zeb1, and endothelin-1. This indicates that mesenchymal phenotype acquisition occurred through an EnMT-like process. Inhibition of TGFb receptor I (TGFbRI) downregulated snail gene expression, blocked the EnMT, and facilitated the differentiation of EPC to the endothelial cell lineage. Furthermore, TGFbRI inhibition decreased migration of EPC stimulated by SMC without affecting their functionality and adhesion capacity. Conclusion These results indicate that EPC may differentiate into SMC-like cells through an EnMT-like process and that TGFbI plays an important role in the fate of EPC.

Oncogene, 2009

Myc and transforming growth factor-b (TGFb) signaling are mutually antagonistic, that is Myc suppresses the activation of TGFb-induced genes, whereas TGFb represses c-myc transcription. Here, we report a positive role for Myc in the TGFb response, consisting in the induction of an epithelial-to-mesenchymal transition (EMT) and the activation of the EMT-associated gene Snail. Knockdown of either Myc or the TGFb effectors SMAD3/4 in epithelial cells eliminated Snail induction by TGFb. Both Myc and SMAD complexes targeted the Snail promoter in vivo, DNA binding occurring in a mutually independent manner. Myc was bound prior to TGFb treatment, and was required for rapid Snail activation upon SMAD binding induced by TGFb. On the other hand, c-myc downregulation by TGFb was a slower event, occurring after Snail induction. The response of Snail to another cytokine, hepatocyte growth factor (HGF), also depended on Myc and SMAD4. Thus, contrary to their antagonistic effects on Cip1 and INK4b, Myc and SMADs cooperate in signal-dependent activation of Snail in epithelial cells. Although Myc also targeted the Snail promoter in serum-stimulated fibroblasts, it was dispensable for its activation in these conditions, further illustrating that the action of Myc in transcriptional regulation is context-dependent. Our findings suggest that Myc and TGFb signaling may cooperate in promoting EMT and metastasis in carcinomas.

Science Signaling, 2012

Nature cell …, 2000

Cells, 2020