GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells

Amino acid availability is crucial for cancer cells' survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed the Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid pool. The inhibition of GSK3α halts the sourcing of amino acids, which subsequently leads to cancer cell vulnerability toward asparaginase therapy. However, resistance toward GSK3α-mediated protein breakdown can occur, whose underlying mechanism is poorly understood. Here, we set out to define the mechanisms driving dependence toward this degradation machinery upon asparagine starvation in cancer cells. We show the independence of known stress response pathways including the integrated stress response mediated with GCN2. Additionally, we demonstrate the independence of changes in cell cycle progression and expression levels of the asparagine-synthesizing enzyme ASNS. Instead, RNA sequencing revealed that GSK3α inhibition and asparagine starvation leads to the temporally dynamic downregulation of distinct ribosomal proteins, which have been shown to display anti-proliferative functions. Using a CRISPR/Cas9 viability screen, we demonstrate that the downregulation of these specific ribosomal proteins can rescue cell death upon GSK3α inhibition and asparagine starvation. Thus, our findings suggest the vital role of the previously unrecognized regulation of ribosomal proteins in bridging GSK3α activity and tolerance of asparagine starvation

Team consolidation, social integration and scientists’ research performance: An empirical study in the Biology and Biomedicine field

This is an author post-print (ie final draft post-refereeing) of the paper accepted for publication in Scientometrics 76 (3), 2008. The original publication is available at www.springerlink.com [http://www.springerlink.com/content/0138-9130]The effects of team consolidation and social integration on individual scientists’ activity and performance were investigated by analysing the relationships between these factors and scientists’ productivity, impact, collaboration patterns, participation in funded research projects and programs, contribution to the training of junior researchers, and prestige. Data were obtained from a survey of researchers ascribed to the Biology and Biomedicine area of the Spanish Council for Scientific Research, and from their curricula vitae. The results show that high levels of team consolidation and of integration of the scientist within his or her team are factors which might help create the most favourable social climate for research performance and productivity. Researchers who carried out their activity in a social climate characterized by these factors participated in more domestic research projects and supervised more doctoral dissertations than the rest of their colleagues. They were also more productive, as shown by the higher number of papers published in journals included in the Journal Citation Reports and the higher number of patents granted. These metrics are the main indicators taken into account in the evaluation of the research activity of Spanish scientists, and are therefore the activities that scientists invest the most energy in with a view to obtaining professional recognition. The results corroborate the importance of research teamwork, and draw attention to the importance of teamwork understood not as two or more scientists working together to solve a problem, but as a complex process involving interactions and interpersonal relations within a particular contextual framework.RESUMEN. Se investigan los efectos de la consolidación de los equipos y de la integración social de los individuos, sobre distintos aspectos de la actividad investigadora y el rendimiento de los científicos: productividad, impacto, pautas de colaboración, participación en programas y proyectos de I+D financiados, contribución a la formación de jóvenes investigadores y prestigio. Los datos proceden de una encuesta realizada a los investigadores adscritos al área de Biología y Biomedicina del Consejo Superior de Investigaciones Científicas, así como de sus curricula vitae. Los resultados muestran que elevados niveles de consolidación grupal y de integración de los científicos en el seno de sus equipos, son factores que pueden contribuir a crear el clima social más favorable para el rendimiento y la productividad científica. Los investigadores que desarrollaron su actividad en un clima social caracterizado por estos factores, participaron en un mayor número de más proyectos de investigación nacionales qy dirigieron más tesis doctorales, que el resto de sus colegas. Asimismo, fueron más productivos, tanto en número de artículos en revistas incluidas en el Journal Citation Reports como de patentes concedidas. Estos son los principales indicadores considerados a la hora de evaluar la actividad investigadora de los científicos españoles en este y otros campos científicos, y como consecuencia son las actividades a las que dedican mayor empeño, con el fin de conseguir mayor reconocimiento profesional de su trabajo. Los resultados corroboran la importancia del trabajo de investigación en equipo, y llaman la atención sobre la importancia del trabajo en equipo entendido no como dos o más científicos que trabajan juntos en la solución de un determinado problema, sino como un proceso complejo que implica interacciones y relaciones personales en el seno de un determinado marco contextual.The study reported in this paper was done as part of the research project titled ‘Consolidation and cohesion of CSIC research teams and their influence on the research activity and performance of their components’ (CSIC intramural project 200410E051) El estudio ha sido realizado en el marco del proyecto de investigación Consolidación y cohesión de los equipos de investigación del CSIC y su influencia sobre la actividad investigadora y el rendimiento de sus componentes. Área de Biología y Biomedicina' financiado por el CSIC (Proyecto intramural 200410E051)Peer reviewe

Supramolecular assembly of GSK3α as a cellular response to amino acid starvation

The tolerance of amino acid starvation is fundamental to robust cellular fitness. Asparagine depletion is lethal to some cancer cells, a vulnerability that can be exploited clinically. We report that resistance to asparagine starvation is uniquely dependent on an N-terminal low-complexity domain of GSK3α, which its paralog GSK3β lacks. In response to depletion of specific amino acids, including asparagine, leucine, and valine, this domain mediates supramolecular assembly of GSK3α with ubiquitin-proteasome system components in spatially sequestered cytoplasmic bodies. This effect is independent of mTORC1 or GCN2. In normal cells, GSK3α promotes survival during essential amino acid starvation. In human leukemia, GSK3α body formation predicts asparaginase resistance, and sensitivity to asparaginase combined with a GSK3α inhibitor. We propose that GSK3α body formation provides a cellular mechanism to maximize the catalytic efficiency of proteasomal protein degradation in response to amino acid starvation, an adaptive response co-opted by cancer cells for asparaginase resistance