| Autor: |
Iacovella MG; Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy., Bremang M; Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.; Current address: Proteome Sciences Plc, Hamilton House, Mabledon Place, London, United Kingdom., Basha O; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, POB 653, Beer-Sheva 84105, Israel., Giacò L; Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy., Carotenuto W; The FIRC Institute of Molecular Oncology (IFOM), Via Adamello 16, 20139 Milan, Italy., Golfieri C; Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy., Szakal B; The FIRC Institute of Molecular Oncology (IFOM), Via Adamello 16, 20139 Milan, Italy., Dal Maschio M; Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy., Infantino V; Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy., Beznoussenko GV; The FIRC Institute of Molecular Oncology (IFOM), Via Adamello 16, 20139 Milan, Italy., Joseph CR; The FIRC Institute of Molecular Oncology (IFOM), Via Adamello 16, 20139 Milan, Italy., Visintin C; Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy., Mironov AA; The FIRC Institute of Molecular Oncology (IFOM), Via Adamello 16, 20139 Milan, Italy., Visintin R; Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy., Branzei D; The FIRC Institute of Molecular Oncology (IFOM), Via Adamello 16, 20139 Milan, Italy.; Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (CNR), Via Abbiategrasso 207, 27100 Pavia, Italy., Ferreira-Cerca S; Lehrstuhl für Biochemie III, Universität Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany., Yeger-Lotem E; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, POB 653, Beer-Sheva 84105, Israel., De Wulf P; Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.; Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy. |
| Abstrakt: |
The Saccharomyces cerevisiae kinase/adenosine triphosphatase Rio1 regulates rDNA transcription and segregation, pre-rRNA processing and small ribosomal subunit maturation. Other roles are unknown. When overexpressed, human ortholog RIOK1 drives tumor growth and metastasis. Likewise, RIOK1 promotes 40S ribosomal subunit biogenesis and has not been characterized globally. We show that Rio1 manages directly and via a series of regulators, an essential signaling network at the protein, chromatin and RNA levels. Rio1 orchestrates growth and division depending on resource availability, in parallel to the nutrient-activated Tor1 kinase. To define the Rio1 network, we identified its physical interactors, profiled its target genes/transcripts, mapped its chromatin-binding sites and integrated our data with yeast's protein-protein and protein-DNA interaction catalogs using network computation. We experimentally confirmed network components and localized Rio1 also to mitochondria and vacuoles. Via its network, Rio1 commands protein synthesis (ribosomal gene expression, assembly and activity) and turnover (26S proteasome expression), and impinges on metabolic, energy-production and cell-cycle programs. We find that Rio1 activity is conserved to humans and propose that pathological RIOK1 may fuel promiscuous transcription, ribosome production, chromosomal instability, unrestrained metabolism and proliferation; established contributors to cancer. Our study will advance the understanding of numerous processes, here revealed to depend on Rio1 activity. |
