Suchergebnisse

The fast dynamics and reversibility of posttranslational modifications by the ubiquitin family pose significant challenges for research. Here we present SUMO-ID, a technology that merges proximity biotinylation by TurboID and protein-fragment complementation to find SUMO-dependent interactors of proteins of interest. We develop an optimized split-TurboID version and show SUMO interaction-dependent labelling of proteins proximal to PML and RANGAP1. SUMO-dependent interactors of PML are involved in transcription, DNA damage, stress response and SUMO modification and are highly enriched in SUMO Interacting Motifs, but may only represent a subset of the total PML proximal proteome. Likewise, SUMO-ID also allow us to identify interactors of SUMOylated SALL1, a less characterized SUMO substrate. Furthermore, using TP53 as a substrate, we identify SUMO1, SUMO2 and Ubiquitin preferential interactors. Thus, SUMO-ID is a powerful tool that allows to study the consequences of SUMO-dependent interactions, and may further unravel the complexity of the ubiquitin code. ; We are thankful to Iraide Escobes for her work in the Proteomics Platform at CIC bioGUNE and Arnoud de Ru in the Center for Proteomics and Metabolomics at the LUMC. O.B.-G., F.T., R.B. and A.C.O.V. acknowledge funding by the grant 765445-EU (UbiCODE Program). R.B. acknowledges funding by grants BFU2017-84653-P and PID2020-114178GB-I00 (MINECO/FEDER, EU), SEV-2016-0644 (Severo Ochoa Excellence Program), SAF2017-90900-REDT (UBIRed Program) and IT1165-19 (Basque Country Government). Additional support was provided by the Department of Industry, Tourism, and Trade of the Basque Country Government (Elkartek Research Programs) and by the Innovation Technology Department of the Bizkaia County. VM acknowledges FPI grant PRE2018-086230 (MINECO/FEDER, EU). F.E. is at Proteomics Platform, member of ProteoRed-ISCIII (PT13/0001/0027). F.E. and A.M.A. acknowledge CIBERehd. A.C. acknowledges the Basque Department of education (IKERTALDE IT1106-16), the MCIU ...

Altres ajuts: NM-M was supported by the Spanish Association Against Cancer (AECC), AECC JP Vizcaya. VT is supported by Fundación Vasca de Innovación e Investigación Sanitarias, BIOEF (BIO15/CA/052), the department of health of the Basque Government (2016111109) and the 2016 grant of the AECC (Junta provincial de Bizkaia). LA, AA-A and LV-J were supported by the Basque Government of education. The work of A.C. is supported by the Ramón y Cajal award, the Basque Department of Industry, Tourism and Trade (Etortek) and the department of education (IKERTALDE IT1106-16), FERO VIII Fellowship, the BBVA foundation, Severo Ochoa. Excellence Accreditation SEV-2016-0644) and the European Research Council (Starting Grant 336343; Proof of Concept 754627). The participation of AC, VT, NM-M, SF and AZ as part of CIBERONC was co-funded with FEDER funds. ; Prostate cancer is diagnosed late in life, when co-morbidities are frequent. Among them, hypertension, hypercholesterolemia, diabetes or metabolic syndrome exhibit an elevated incidence. In turn, prostate cancer patients frequently undergo chronic pharmacological treatments that could alter disease initiation, progression and therapy response. Here we show that treatment with anti-cholesterolemic drugs, statins, at doses achieved in patients, enhance the pro-tumorigenic activity of obesogenic diets. In addition, the use of a mouse model of prostate cancer and human prostate cancer xenografts revealed that in vivo simvastatin administration alone increases prostate cancer aggressiveness. In vitro cell line systems supported the notion that this phenomenon occurs, at least in part, through the direct action on cancer cells of low doses of statins, in range of what is observed in human plasma. In sum, our results reveal a prostate cancer experimental system where statins exhibit an undesirable effect, and warrant further research to address the relevance and implications of this observation in human prostate cancer.

Altres ajuts: V. Torrano is funded by Fundación Vasca de Innovación e Investigación Sanitarias, Bioef (BIO15/CA/052), the Fundación Científica Asociación Española Contra el Cáncer J.P. Bizkaia, and the Basque Department of Health (2016111109). The work of A. Carracedo is supported by the Basque Department of Industry, Tourism and Trade (Elkartek), the Department of Education (IKERTALDE IT1106-16, with A. Gomez-Muñoz), the Department of Health (2019222031), the Fundación BBVA, FEDER [European Regional Development Fund, EU]; the Fundación Científica Asociación Española Contra el Cáncer (IDEAS175CARR; GCTRA18006CARR, with M. Graupera and R.R. Gomis), "La Caixa" Foundation (HR17-00094), and the European Research Council (Starting Grant , PoC , and Consolidator Grant 819242). G. Velasco's research is funded by Fundació la Marató de TV3 (20134031). R.R. Gomis is supported by "La Caixa" Foundation (HR17-00092). CIBERONC was cofunded with European Regional Development funds and funded by Instituto de Salud Carlos III. L. Valcarcel-Jimenez was funded by a Basque Government predoctoral grant. ; This study unravels an unprecedented murine model of lethal metastatic prostate cancer, based on the combined deletion of Pten and Lkb1. Importantly, minimal activity of LKB1 is sufficient to hamper prostate cancer cell aggressiveness, thus redefining the relationship between gene dosage and tumor suppression. Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly ...