The era of high-quality chemical probes.

Small-molecule chemical probes are among the most important tools to study the function of proteins in cells and organisms. Regrettably, the use of weak and non-selective small molecules has generated an abundance of erroneous conclusions in the scientific literature. More recently, minimal criteria have been outlined for investigational compounds, encouraging the selection and use of high-quality chemical probes. Here, we briefly recall the milestones and key initiatives that have paved the way to this new era, illustrate examples of recent high-quality chemical probes and provide our perspective on future challenges and developments

Is Xanthomonas citri subsp. citri (Xcc) knocking at the doors of the Mediterranean basin?

Mediterranean basin is free of Citrus Bacterial Canker (CBC) a citrus disease caused by Xanthomonas citri subsp. citri (Xcc) and X. fuscans subsp. auratifolii (Xfa). ln 2014, EFSA highlighted ornamental rutaceous species (ORS) as possible pathway for CBC entry. ORPRAMed research project is underway to evaluate the risk of introduction of Xcc and Xfa through ORS in Europe. ORPRAMed partners are focusing on ORS not covered by 2000/29EC Directive through phytopatological, molecular, genetic, detection and economic approaches. Herein, we have analysed the trade flows in vegetal material for non-food uses. In particular, we have considered the import flows from countries where Xcc is classified as present. From UN-ComTrade dataset (2015), with Code 06, Mediterranean countries reported to introduce over 8.7 million kg from areas where Xcc is present, for an overall value of 46.0 million $. We also have to include here the re-exportation of plant material, from these countries, originated formerly in other areas that is estimated in 156,384 kg for a value of 0.276 million$. Moreover, within the project a field survey was conducted in Turkey in order to exclude the presence of CBC, due to its vicinity to infected areas. In the survey carried out in Adana, Mersin and Hatay provinces, 61 commercial nurseries and about 8500 hectares of citrus orchards were screened and disease symptoms were not observed. In the same context, growers and the nurserymen were informed about the possible introduction risk of this severe citrus disease. (Résumé d'auteur

NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation.

Breast cancer is genetically heterogeneous, and recent studies have underlined a prominent contribution of epigenetics to the development of this disease. To uncover new synthetic lethalities with known breast cancer oncogenes, we screened an epigenome-focused short hairpin RNA library on a panel of engineered breast epithelial cell lines. Here we report a selective interaction between the NOTCH1 signaling pathway and the SUMOylation cascade. Knockdown of the E2-conjugating enzyme UBC9 (UBE2I) as well as inhibition of the E1-activating complex SAE1/UBA2 using ginkgolic acid impairs the growth of NOTCH1-activated breast epithelial cells. We show that upon inhibition of SUMOylation NOTCH1-activated cells proceed slower through the cell cycle and ultimately enter apoptosis. Mechanistically, activation of NOTCH1 signaling depletes the pool of unconjugated small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 leading to increased sensitivity to perturbation of the SUMOylation cascade. Depletion of unconjugated SUMO correlates with sensitivity to inhibition of SUMOylation also in patient-derived breast cancer cell lines with constitutive NOTCH pathway activation. Our investigation suggests that SUMOylation cascade inhibitors should be further explored as targeted treatment for NOTCH-driven breast cancer.Oncogene advance online publication, 29 September 2014; doi:10.1038/onc.2014.319

NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation.

Breast cancer is genetically heterogeneous, and recent studies have underlined a prominent contribution of epigenetics to the development of this disease. To uncover new synthetic lethalities with known breast cancer oncogenes, we screened an epigenome-focused short hairpin RNA library on a panel of engineered breast epithelial cell lines. Here we report a selective interaction between the NOTCH1 signaling pathway and the SUMOylation cascade. Knockdown of the E2-conjugating enzyme UBC9 (UBE2I) as well as inhibition of the E1-activating complex SAE1/UBA2 using ginkgolic acid impairs the growth of NOTCH1-activated breast epithelial cells. We show that upon inhibition of SUMOylation NOTCH1-activated cells proceed slower through the cell cycle and ultimately enter apoptosis. Mechanistically, activation of NOTCH1 signaling depletes the pool of unconjugated small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 leading to increased sensitivity to perturbation of the SUMOylation cascade. Depletion of unconjugated SUMO correlates with sensitivity to inhibition of SUMOylation also in patient-derived breast cancer cell lines with constitutive NOTCH pathway activation. Our investigation suggests that SUMOylation cascade inhibitors should be further explored as targeted treatment for NOTCH-driven breast cancer.Oncogene advance online publication, 29 September 2014; doi:10.1038/onc.2014.319