Translational control of gene expression in normal human cells and in pathological conditions
We are interested in the study of posttranscriptional regulation of gene expression. It is currently estimated that translation controls a large portion of gene expression by restricting protein synthesis to specific mRNAs. We have isolated eIF6, an initiation factor that regulates metabolism at the level of translation, and it is rate-limiting for cellular growth. Multidisciplinary projects address the role of eIF6 in development and disease, and its activity in Shwachman Diamond Syndrome.
The study of translation is extended to human cells from the immune system and from several neoplastic diseases, including multiple myeloma and malignant mesothelioma. By combining cell biology, biochemistry and molecular biology, we aim at the definition of mechanistic steps of translational control that drive pathological phenomena and can become a therapeutic target.
Diverse proteine che regolano la traduzione sono coinvolte nella tumorigenesi e possono essere bersaglio di farmaci. Il nostro Gruppo si concentra sullo studio di un particolare fattore che regola l’inizio della traduzione, eIF6. L’attività di eIF6 è essenziale sia per generare nuovi ribosomi sia per avere una traduzione efficiente. eIF6 è presente ad alti livelli in differenti tipi di tumore dove controlla la traduzione, la crescita e la trasformazione tumorale delle cellule. Una riduzione del 50% di eIF6 limita la tumorigenicità delle cellule senza compromettere la vitalità delle cellule non tumorali. Il nostro laboratorio sta producendo nuovi modelli in topo per studiare il ruolo di eIF6 nella tumorigenesi e caratterizzare i segnali molecolari che regolano l’inizio della traduzione. Un ulteriore obiettivo è quello di scoprire inibitori farmacologici dell’attività di eIF6 con potenziale terapeutico in pazienti oncologici. Visto l’ampio impatto di eIF6 sulla traduzione, i nostri studi si estendono ad altre proteine coinvolte nell’attività ribosomale e nella regolazione dell’mRNA.
Projects
- Characterization of Fam46c tumor suppressor protein in multiple myeloma.
- Role of miRNAs in translational control of malignant mesothelioma.
- Development of new models to study translation in human cancer cells and in the human immune system.
- Definition of therapeutic targets in Shwachman Diamond Syndrome
- Therapeutic modulation of the Shwachman Diamond Syndrome (SDS) phenotype
Team
Nome / Name | Ruolo / Role | |
---|---|---|
Nicola Manfrini, PhD | Post Doc | manfrini@ingm.org |
Annarita Miluzio | Laboratory Technician | miluzio@ingm.org |
Giada Mori | Student | mori@ingm.org |
Stefania Oliveto, PhD | Post Doc | oliveto@ingm.org |
Sara Ricciardi, PhD | Post Doc | ricciardi@ingm.org |
Paolo Ritter | Student | ritter@ingm.org |
Publications
- Ribosome profiling unveils translational regulation of metabolic enzymes in primary CD4+ Th1 cells
Manfrini N, Ricciardi S, Alfieri R, Ventura G, Calamita P, Favalli A, Biffo S.
Dev Comp Immunol. 2020 Aug;109:103697. Epub 2020 Apr 21 - The Translational Machinery of Human CD4+ T Cells Is Poised for Activation and Controls the Switch from Quiescence to Metabolic Remodeling.
Ricciardi S, Manfrini N, Alfieri R, Calamita P, Crosti MC, Simone G, Müller R, Pagani M, Abrignani S, Biffo S.
Cell Metab. 2018 Aug 29. pii: S1550-4131(18)30510-2. doi: 10.1016/j.cmet.2018.08.009. [Epub ahead of print] - A polysome-based microRNA screen identifies miR-24-3p as a novel pro-migratory miRNA in mesothelioma.
Oliveto S, Alfieri R, Miluzio A, Scagliola A, Seclì RS, Gasparini P, Grosso S, Cascione L, Mutti L, Biffo S.
Cancer Res. (Aug 2018) pii: canres.0655.2018 [Epub ahead of print] - SBDS-Deficient Cells Have an Altered Homeostatic Equilibrium due to Translational Inefficiency Which Explains their Reduced Fitness and Provides a Logical Framework for Intervention.
Calamita P, Miluzio A, Russo A, Pesce E, Ricciardi S, Khanim F, Cheroni C, Alfieri R, Mancino M, Gorrini C, Rossetti G, Peluso I, Pagani M, Medina DL, Rommens J, Biffo S.
PLoS Genet (2017) 13:e1006552 - Human macrophage ferroportin biology and the basis for the ferroportin disease.
Sabelli M, Montosi G, Garuti C, Caleffi A, Oliveto S, Biffo S, Pietrangelo A.
Hepatology (2017) 65:1512-1525 - mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex.
Pema M, Drusian L, Chiaravalli M, Castelli M, Yao Q, Ricciardi S, Somlo S, Qian F, Biffo S, Boletta A.
Nat Commun (2016) 7:10786 - eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription.
Brina D, Miluzio A, Ricciardi S, Clarke K, Davidsen PK, Viero G, Tebaldi T, Offenhauser N, Rozman J, Rathkolb B, Neschen S, Klingenspor M, Wolf E, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Quattrone A, Falciani F, Biffo S.
Nat Commun (2015) 6:8261 - Eukaryotic translation initiation factor 6 is a novel regulator of reactive oxygen species-dependent megakaryocyte maturation.
Ricciardi S, Miluzio A, Brina D, Clarke K, Bonomo M, Aiolfi R, Guidotti LG, Falciani F, Biffo S.
J Thromb Haemost (2015) 13:2108-18 - The ribonuclease DIS3 promotes let-7 miRNA maturation by degrading the pluripotency factor LIN28B mRNA.
Segalla S, Pivetti S, Todoerti K, Chudzik MA, Giuliani EC, Lazzaro F, Volta V, Lazarevic D, Musco G, Muzi-Falconi M, Neri A, Biffo S, Tonon G.
Nucleic Acids Res (2015) 43:5182-93 - Translation factors and ribosomal proteins control tumor onset and progression: how?
Loreni F, Mancino M, Biffo S.
Oncogene (2014) 33:2145-56 - RACK1 depletion in a mouse model causes lethality, pigmentation deficits and reduction in protein synthesis efficiency.
Volta V, Beugnet A, Gallo S, Magri L, Brina D, Pesce E, Calamita P, Sanvito F, Biffo S.
Cell Mol Life Sci (2013) 70:1439-50 - Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat.
Carrieri C, Cimatti L, Biagioli M, Beugnet A, Zucchelli S, Fedele S, Pesce E, Ferrer I, Collavin L, Santoro C, Forrest AR, Carninci P, Biffo S, Stupka E, Gustincich S.
Nature (2012) 491:454-7 - Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth.
Miluzio A, Beugnet A, Grosso S, Brina D, Mancino M, Campaner S, Amati B, de Marco A, Biffo S.
Cancer Cell (2011) 19:765-75