Prof. Tuosto's research involves the fields of Cellular and Molecular Biology and Immunology. In the last 15 years her research activity has contributed to the development of well-characterized systems to analyze the signal transduction pathways involved in T cell activation and apoptosis.The analysis of apoptosis induction was initiated since 1994 and allowed the clarification of signals regulating the susceptibility of T cells to apoptosis induced by several stimuli, including immunosuppressive drugs and HIV-1. The work of Tuosto's group in the last 8 years has also contributed to the characterization of the molecules involved in coupling membrane receptors to the activation of the survival transcription factor NF-kB. Specific chromatin immunoprecipitation (ChIP) techniques have been developed to analyse the recruitment of several transcription factors (NF-kB, p53 and p73) to target genes and relate the occupancy of target gene promoters with the transcriptional activation of anti-apoptotic (Bcl-xL) and/or repression of pro-apoptotic (Bax) genes of the Bcl-2 family. More recently, Tuosto's research focused on the characterization of the signalling pathways regulating mitochondria-dependent and Bax-regulated apoptosis in response to chemotherapeutic drugs, and on the role of either p53 or p73 proteins in the acquisition of resistance to apoptosis by tumour cells. These studies contributed to the identification of a new tumour-associated mutantof p53 (K351N) involved in the acquisition of resistance to apoptosis in ovarian cancers. More recently, our research has been aimed to provide biological bases for immunotherapeutic approaches targeting CD28/PI3K in order to dampen the inflammatory response in Multiple Sclerosis.
Students and Post Doc
Martina Kunkl: PhD student
- Porciello N, Kunkl M, Tuosto L. CD28 between tolerance and autoimmunity: the side effects of animal models. F1000Research 2018, 7(F1000 Faculty Rev):682
- Porciello N, Grazioli P, Campese AF, Kunkl M, Caristi S, Mastrogiovanni M, Muscolini M, Spadaro F, Favre C, Nunès JA, Borroto A, Alarcon B, Screpanti I, Tuosto L. A non-conserved amino acid variant regulates differential signalling between human and mouse CD28. Nat Commun. 2018 Mar 14;9(1):1080
- Kunkl M, Porciello N, Mastrogiovanni M, Capuano C, Lucantoni F, Moretti C, Persson JL, Galandrini R, Buzzetti R, Tuosto L. ISA-2011B, a Phosphatidylinositol 4-Phosphate 5-Kinase α Inhibitor, impairs CD28-dependent costimulatory and pro-inflammatory signals in human T lymphocytes. Front Immunol. 2017 Apr 26;8:502. doi: 10.3389/fimmu.2017.00502. eCollection 2017.
- Porciello N, Tuosto L. CD28 costimulatory signals in T lymphocyte activation: Emerging functions beyond a qualitative and quantitative support to TCR signalling. Cytokine Growth Factor Rev. 2016 Mar 4. pii: S1359-6101(16)30021-1
- Kallikourdis M, Trovato AE, Roselli G, Muscolini M, Porciello N, Tuosto L, Viola A. Phosphatidylinositol 4-phosphate 5-kinase b controls recruitment of lipid rafts into the Immunological Synapse. J Immunol. 2016 Feb 15;196(4):1955-63
- Tuosto L, Capuano C, Muscolini M, Santoni A, Galandrini R. The multifaceted role of PIP2 in leukocyte biology. Cell Mol Life Sci. 2015 Dec;72(23):4461-74
- Tuosto L. Targeting Inflammatory T Cells in Multiple Sclerosis: Current Therapies and Future Challenges. Austin J Mult Scler & Neuroimmunol. 2015;2(1): 1009.
- Muscolini M, Camperio C, Porciello N, Caristi S, Capuano C, Viola A, Galandrini R, Tuosto L. Phosphatidylinositol 4-phosphate 5-kinase a and Vav1 mutual cooperation in CD28-mediated actin remodeling and signaling functions. J Immunol. 2015 Feb 1;194(3):1323-33.
- Colasanti T, Vomero M, Alessandri C, Barbati C, Maselli A, Camperio C, Conti F, Tinari A, Carlo-Stella C, Tuosto L, Benincasa D, Valesini G, Malorni W, Pierdominici M, Ortona E. Role of alpha-synuclein in autophagy modulation of primary human T lymphocytes. Cell Death Dis. 2014 May 29;5:e1265.
- Camperio, C., M. Muscolini, E. Volpe, D. Di Mitri, R. Mechelli, M. C. Buscarinu, S. Ruggieri, E. Piccolella, M. Salvetti, C. Gasperini, L. Battistini, and L. Tuosto. 2014. CD28 ligation in the absence of TCR stimulation up-regulates IL-17A and pro-inflammatory cytokines in relapsing-remitting multiple sclerosis T lymphocytes. Immunol Lett 158:134-142.
- Muscolini M, Camperio C, Capuano C, Caristi S, Piccolella E, Galandrini R, Tuosto L. Phosphatidylinositol 4-phosphate 5-kinase aactivation critically contributes to CD28-dependent signaling responses. J Immunol. 2013 May 15;190(10):5279-86.
- Muscolini M, Montagni E, Palermo V, Di Agostino S, Gu W, Abdelmoula-Soussi S, Mazzoni C, Blandino G and Tuosto L. The cancer-associated K351N mutation affects the ubiquitination and the translocation to mitochondria of p53 protein. J Biol Chem. 2011 Nov18;286(46):39693-702.
- Muscolini M, Montagni E, Caristi S, Nomura T, Kamada R, Di Agostino S, Corazzari M, Piacentini M, Blandino G, Costanzo A, Sakaguchi K, Tuosto L. Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain. Cell Cycle. 2009 Oct 15;8(20):3396-405
- Muscolini M, Cianfrocca R, Sajeva A, Mozzetti S, Ferrandina G, Costanzo A, Tuosto L. Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells. Mol Cancer Ther. 2008 Jun;7(6):1410-9
- Annibaldi A, Sajeva A, Muscolini M, Ciccosanti F, Corazzari M, Piacentini M, Tuosto L. CD28 ligation in the absence of TCR promotes RelA/NF-kappaB recruitment and trans-activation of the HIV-1 LTR. Eur J Immunol. 2008 May;38(5):1446-51.
- Cianfrocca R, Muscolini M, Marzano V, Annibaldi A, Marinari B, Levrero M, Costanzo A, Tuosto L. RelA/NF-kappaB recruitment on the bax gene promoter antagonizes p73-dependent apoptosis in costimulated T cells. Cell Death Differ. 2008 Feb;15(2):354-63.
- Tavano R, Contento RL, Baranda SJ, Soligo M, Tuosto L, Manes S, Viola A. CD28 interaction with filamin-A controls lipid raft accumulation at the T-cell immunological synapse. Nat Cell Biol. 2006 Nov;8(11):1270-6.
- Marinari B, Costanzo A, Marzano V, Piccolella E, Tuosto L. CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-kappaB subunits on IL-8 and Bcl-xL gene promoters. Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6098-103.
- Piccolella E, Spadaro F, Ramoni C, Marinari B, Costanzo A, Levrero M, Thomson L, Abraham RT, Tuosto L. Vav-1 and the IKK alpha subunit of I kappa B kinase functionally associate to induce NF-kappa B activation in response to CD28 engagement. J Immunol. 2003 Mar 15;170(6):2895-903.
- Tuosto L, Marinari B, Piccolella E. CD4-Lck through TCR and in the absence of Vav exchange factor induces Bax increase and mitochondrial damage. J Immunol. 2002 Jun 15;168(12):6106-12.
- Marinari B, Costanzo A, Viola A, Michel F, Mangino G, Acuto O, Levrero M, Piccolella E, Tuosto L. Vav cooperates with CD28 to induce NF-kappaB activation via a pathway involving Rac-1 and mitogen-activated kinase kinase 1. Eur J Immunol. 2002 Feb;32(2):447-56.
- Tuosto L, Costanzo A, Guido F, Marinari B, Vossio S, Moretti F, Levrero M, Piccolella E. Mitogen-activated kinase kinase kinase 1 regulates T cell receptor- and CD28-mediated signaling events which lead to NF-kappaB activation. Eur J Immunol. 2000 Sep;30(9):2445-54.
- Tuosto L, Acuto O. CD28 affects the earliest signaling events generated by TCR engagement. Eur J Immunol. 1998 Jul;28(7):2131-42.
- Tuosto L, Michel F, Acuto O. p95vav associates with tyrosine-phosphorylated SLP-76 in antigen-stimulated T cells. J Exp Med. 1996 Sep 1;184(3):1161-6.
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