Deregulated translation control is a hallmark of human cancers and is critical for tumorigenesis downstream of multiple oncogenic signaling pathways. eIF6 is an oncogenic translation factor, which regulates the initiation phase of translation controlling active 80S complex formation. eIF6 depletion and dephosphorylation slow cell growth and cell transformation in vitro and protect from tumor development in mice. eIF6 activation is mTORC1-independent and driven by PKCβ mediated phosphorylation on Ser235. Intriguingly, both eIF6 overexpression and PKC hyperactivation are found in T-cell lymphomas, such as in Anaplastic Large Cell Lymphoma (ALCL). We hypothesized that eIF6 phosphorylation drives T cell lymphomagenesis and mammalian development. We used a conditional eIF6SA KI mouse model in which Ser235 is replaced by an Ala. We discovered that homozygous point mutation (eIF6SA/SA) is lethal after gastrulation. Heterozygous mice (eIF6SA/+) are viable but resistant to NPM-ALK induced lymphomagenesis. The survival of eIF6SA/SA NPM-ALK mice is significantly increased and the appearance of lymphoma is delayed up to 6 months. Surprisingly, ex vivo eIF6SA/SA NPM-ALK primary thymocytes have a striking senescence-like phenotype. Similarly, in vitro generated eIF6SA/SA MEFs show a markedly reduced proliferation and increased senescence. This phenotype is completely rescued by transducing eIF6wt, but not by eIF6SA. In eIF6SA/SA MEFs, the direct interaction between mutant eIF6SA protein with the 60S ribosomal subunit surface is extremely increased, suggesting that 60S viability, required for active translation, could be compromised. In conclusion, our work demonstrates for the first time that eIF6 phosphorylation on Ser235 is essential for mammalian development, cell homeostasis and is rate-limiting for T-cell lymphomagenesis in vivo. Finally, we suggest that the translational control driven by eIF6 activity induces cellular premature senescence, resulting in a protective mechanism against tumor progression.

EIF6 PHOSPHORYLATION ON SER235 IS REQUIRED FOR MAMMALIAN DEVELOPMENT AND FOR T-CELL LYMPHOMAGENESIS, ESTABLISHING A FUNCTIONAL NETWORK BETWEEN TRANSLATION AND SENESCENCE / A. Scagliola ; tutor: S. Biffo ; supervisor: A. Miluzio. - : . DIPARTIMENTO DI BIOSCIENZE, 2019 Mar 14. ((31. ciclo, Anno Accademico 2018. [10.13130/scagliola-alessandra_phd2019-03-14].

EIF6 PHOSPHORYLATION ON SER235 IS REQUIRED FOR MAMMALIAN DEVELOPMENT AND FOR T-CELL LYMPHOMAGENESIS, ESTABLISHING A FUNCTIONAL NETWORK BETWEEN TRANSLATION AND SENESCENCE.

A. Scagliola
2019-03-14

Abstract

Deregulated translation control is a hallmark of human cancers and is critical for tumorigenesis downstream of multiple oncogenic signaling pathways. eIF6 is an oncogenic translation factor, which regulates the initiation phase of translation controlling active 80S complex formation. eIF6 depletion and dephosphorylation slow cell growth and cell transformation in vitro and protect from tumor development in mice. eIF6 activation is mTORC1-independent and driven by PKCβ mediated phosphorylation on Ser235. Intriguingly, both eIF6 overexpression and PKC hyperactivation are found in T-cell lymphomas, such as in Anaplastic Large Cell Lymphoma (ALCL). We hypothesized that eIF6 phosphorylation drives T cell lymphomagenesis and mammalian development. We used a conditional eIF6SA KI mouse model in which Ser235 is replaced by an Ala. We discovered that homozygous point mutation (eIF6SA/SA) is lethal after gastrulation. Heterozygous mice (eIF6SA/+) are viable but resistant to NPM-ALK induced lymphomagenesis. The survival of eIF6SA/SA NPM-ALK mice is significantly increased and the appearance of lymphoma is delayed up to 6 months. Surprisingly, ex vivo eIF6SA/SA NPM-ALK primary thymocytes have a striking senescence-like phenotype. Similarly, in vitro generated eIF6SA/SA MEFs show a markedly reduced proliferation and increased senescence. This phenotype is completely rescued by transducing eIF6wt, but not by eIF6SA. In eIF6SA/SA MEFs, the direct interaction between mutant eIF6SA protein with the 60S ribosomal subunit surface is extremely increased, suggesting that 60S viability, required for active translation, could be compromised. In conclusion, our work demonstrates for the first time that eIF6 phosphorylation on Ser235 is essential for mammalian development, cell homeostasis and is rate-limiting for T-cell lymphomagenesis in vivo. Finally, we suggest that the translational control driven by eIF6 activity induces cellular premature senescence, resulting in a protective mechanism against tumor progression.
BIFFO, STEFANO
MILUZIO, ANNARITA
Settore BIO/06 - Anatomia Comparata e Citologia
EIF6 PHOSPHORYLATION ON SER235 IS REQUIRED FOR MAMMALIAN DEVELOPMENT AND FOR T-CELL LYMPHOMAGENESIS, ESTABLISHING A FUNCTIONAL NETWORK BETWEEN TRANSLATION AND SENESCENCE / A. Scagliola ; tutor: S. Biffo ; supervisor: A. Miluzio. - : . DIPARTIMENTO DI BIOSCIENZE, 2019 Mar 14. ((31. ciclo, Anno Accademico 2018. [10.13130/scagliola-alessandra_phd2019-03-14].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/631917
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