The proto-oncogenic protein TAL1 controls TGF-β1 signaling through interaction with SMAD3

AbstractTGF-β1 is involved in many aspects of tissue development and homeostasis including hematopoiesis. The TAL1 transcription factor is also an important player of this latter process and is expressed very early in the myeloid and erythroid lineages. We previously established a link between TGF-β1 signaling and TAL1 by showing that the cytokine was able to induce its proteolytic degradation by the ubiquitin proteasome pathway. In this manuscript we show that TAL1 interacts with SMAD3 that acts in the pathway downstream of TGF-β1 association with its receptor. TAL1 expression strengthens the positive or negative effect of SMAD3 on various genes. Both transcription factors activate the inhibitory SMAD7 factor through the E box motif present in its transcriptional promoter. DNA precipitation assays showed that TAL1 present in Jurkat or K562 cells binds to this SMAD binding element in a SMAD3 dependent manner. SMAD3 and TAL1 also inhibit several genes including ID1, hTERT and TGF-β1 itself. In this latter case TAL1 and SMAD3 can impair the positive effect exerted by E47. Our results indicate that TAL1 expression can modulate TGF-β1 signaling by interacting with SMAD3 and by increasing its transcriptional properties. They also suggest the existence of a negative feedback loop between TAL1 expression and TGF-β1 signaling

Physiological Epidermal Growth Factor Concentrations Activate High Affinity Receptors to Elicit Calcium Oscillations

International audienceSignaling mediated by the epidermal growth factor (EGF) is crucial in tissue development, homeostasis and tumorigenesis. EGF is mitogenic at picomolar concentrations and is known to bind its receptor on high affinity binding sites depending of the oligomerization state of the receptor (monomer or dimer). In spite of these observations, the cellular response induced by EGF has been mainly characterized for nanomolar concentrations of the growth factor, and a clear definition of the cellular response to circulating (picomolar) concentrations is still lacking. We investigated Ca 2+ signaling, an early event in EGF responses, in response to picomolar doses in COS-7 cells where the monomer/dimer equilibrium is unaltered by the synthesis of exogenous EGFR. Using the fluo5F Ca 2+ indicator, we found that picomolar concentrations of EGF induced in 50% of the cells a robust oscillatory Ca 2+ signal quantitatively similar to the Ca 2+ signal induced by nanomolar concentrations. However, responses to nanomolar and picomolar concentrations differed in their underlying mechanisms as the picomolar EGF response involved essentially plasma membrane Ca 2+ channels that are not activated by internal Ca 2+ store depletion, while the nanomolar EGF response involved internal Ca 2+ release. Moreover, while the picomolar EGF response was modulated by charybdotoxin-sensitive K + channels, the nanomolar response was insensitive to the blockade of these ion channels

Malaria Risk Factors in Dielmo, A Senegalese Malaria-Endemic Village, Between October and November of 2013: A Case-Control Study

International audienceThe incidence of malaria has decreased recently in parts of Africa, coinciding with the widespread use of long-lasting insecticide-treated nets (LLINs) and artemisinin-based combination therapy (ACT). This reduction was also observed in Dielmo, our study area, and it was associated with the use of ACT as the first-line treatment against malaria beginning in 2006 and the implementation of LLINs in 2008. However, an unexplained slight increase in malaria incidence was observed in October and November of 2013. The aim of this study was to identify individual and environmental risk factors for malaria using a case-control study approach. Thirty cases and sixty controls were investigated. The use of LLINs was protective against malaria (adjusted odds ratio [AOR] = 0.10; 95% confidence interval [95% CI] = 0.02–0.45; P = 0.003). The risk of malaria transmission was high among villagers who watched television outside the house or the bedroom during the night (AOR = 8.83; 95% CI = 1.39–56.22; P = 0.021). The use of LLINs should be reinforced by the use of individual protection measures to avoid malaria transmission outside of the home. BACKGROUN

Pulse pressure variation and stroke volume variation during increased intra-abdominal pressure: an experimental study

The aim of this study was to evaluate dynamic indices of fluid responsiveness in a model of intra-abdominal hypertension

Synthesis of 3,6-Divinyl-1,2,4,5-Tetrazine, the First Member of the Elusive Vinyltetrazine Family

International audienceThe synthesis of the first vinyltetrazine derivative is ­described. 3,6-Divinyl-1,2,4,5-tetrazine was obtained following a methodology involving cyclization from an imidate and use of 2-phenylsulfonylethyl groups as masked vinyl entities. The first properties of this unique compound are reported