Molecular Histology and Cell Growth

Team

Calamita Piera, Post Doc calamita@ingm.org
Faienza Sipontina, Student,faienza@ingm.org
Gallo Simone, Post Doc gallo@ingm.org
Gatti Guido, Student gatti@ingm.org
Mancino Marilena, PhD Student mancino@ingm.org
Manfrini Nicola, Post Doc manfrini@ingm.org
Miluzio Annarita, Laboratory Technician miluzio@ingm.org
Oliveto Stefania, PhD Student oliveto@ingm.org
Ricciardi Sara, Post Doc ricciardi@ingm.org
Russo Arianna, Graduate fellow russo@ingm.org
Seclì Raissa Serena , Student secli@ingm.org
Scagliola Claudia, PhD Student scagliola@ingm.org

Scientific Background

Our Group is interested to study the molecular mechanisms that regulate translation and are relevant for cancer progression. Our goal is to find new molecular targets for cancer therapy related to translational control, and to develop drugs which hit them. To reach our aim, we are interested in several models from mouse to human cells and Drosophila, through a multidisciplinary approach encompassing biochemistry, cell biology and gene expression analysis.
Protein synthesis (translation) is ratelimiting for growth of cells and tumors. Some translation factors (initiation factors) are involved in tumorigenesis and can be targeted by drugs. We focus on one initiation factor (eIF6). The activity of eIF6 is essential for both the generation of 60S subunits, and for efficient translation. eIF6 is overexpressed in cancer cells and is rate-limiting for growth, translation and transformation of cells. A reduction of 50% of eIF6 reduces tumorigenicity of cells without affecting the viability of normal cells. Notably, eIF6 is acting downstream of the growth factor cascade. Our lab is building new mouse models for studying eIF6 role in transformation, and dissecting the signaling pathways regulating initiation of translation. In addition, we hope to design blockers of eIF6 activity. Due to the pleiotropic effects of eIF6, our studies extend to other regulators of ribosomal activity and gene expression at the posttranscriptional level.

Ongoing Projects

  1. Role of eIF6 in the control of metabolism and cell growth.
  2. Characterization of the RNA binding protein Fam46c.
  3. Translational control in human cells.
  4. Microrna localization in malignant mesothelioma.
  5. Targeting technologies for blocking eIF6.
  6. Function of ribosome-associated RACK1.
  7. Understanding the specificity of tumor cells with mutations of the SBDS gene.
  8. Crosstalk between epigenetics, translation and metabolism.
  9. Role of eIF6 phosphorylation in cancer progression.

Recent Publications

Translation factors and ribosomal proteins control tumor onset and progression: how?
Loreni F, Mancino M, Biffo S.
Oncogene. 2013 May 6. doi: 10.1038/onc.2013.153.

Preclinical demonstration of synergistic Active Nutrients/Drug (AND) combination as a potential treatment for malignant pleural mesothelioma.
Volta V, Ranzato E, Martinotti S, Gallo S, Russo MV, Mutti L, Biffo S, Burlando B.
PLoS One. 2013;8(3):e58051. doi: 10.1371/journal.pone.0058051. Epub 2013 Mar 6.

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 Apr;70(8):1439-50. doi: 10.1007/s00018-012-1215-y. Epub 2012 Dec 2.

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 Nov 15;491(7424):454-7. doi: 10.1038/nature11508. Epub 2012 Oct 14.

Epigallocatechin-3-gallate induces mesothelioma cell death via H2 O2 -dependent T-type Ca2+ channel opening.
Ranzato E, Martinotti S, Magnelli V, Murer B, Biffo S, Mutti L, Burlando B.
J Cell Mol Med. 2012 Nov;16(11):2667-78. doi: 10.1111/j.1582-4934.2012.01584.x.

Growth defects and impaired cognitive-behavioral abilities in mice with knockout for Eif4h, a gene located in the mouse homolog of the Williams-Beuren syndrome critical region.
Capossela S, Muzio L, Bertolo A, Bianchi V, Dati G, Chaabane L, Godi C, Politi LS, Biffo S, D’Adamo P, Mallamaci A, Pannese M.
Am J Pathol. 2012 Mar;180(3):1121-35. doi: 10.1016/j.ajpath.2011.12.008. Epub 2012 Jan 9.

Sensitivity of global translation to mTOR inhibition in REN cells depends on the equilibrium between eIF4E and 4E-BP1.
Grosso S, Pesce E, Brina D, Beugnet A, Loreni F, Biffo S.
PLoS One. 2011;6(12):e29136. doi: 10.1371/journal.pone.0029136. Epub 2011 Dec 22.

Translational control by 80S formation and 60S availability: the central role of eIF6, a rate limiting factor in cell cycle progression and tumorigenesis.
Brina D, Grosso S, Miluzio A, Biffo S.
Cell Cycle. 2011 Oct 15;10(20):3441-6. doi: 10.4161/cc.10.20.17796. Epub 2011 Oct 15.

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 Jun 14;19(6):765-75. doi: 10.1016/j.ccr.2011.04.018.

INGM researches are supported by