Daniela Barilà
e-mail: daniela.barila AT uniroma2.it
affiliation: Università di Roma Tor Vergata
research area(s): Cancer Biology, Molecular Biology
Course:
Cell and Molecular Biology
University/Istitution: Università di Roma Tor Vergata
University/Istitution: Università di Roma Tor Vergata
Birth Date: February 4th 1968 Rome, Italy
Work Address: Department of Biology, University of Rome Tor Vergata
Fondazione Santa Lucia
Via del Fosso di Fiorano 64 - 00143 Rome, Italy
phone: 39-6-501703168
fax: 39-6-501703330
e-mail: daniela.barila@uniroma2.it
EDUCATION
1991: Degree with honours in Biological Sciences, University of Rome "La Sapienza"
1994: Specialization with honours in Biotechnology
POSTGRADUATE EDUCATION AND POSITION HELD
1991-1994: Specialization Fellow, National Institute for Nutrition (INRAN), Rome, Italy.
1993: Visiting fellow, Prof. T. Morimoto"s lab., Cell Biology Dep., New York University, NY, USA
1995-1999: Postdoctoral fellow, Dr. G. Superti Furga"s Lab, Cell Regulation Dep., European Molecular Biology Laboratory (E.M.B.L.), Heidelberg, Germany.
2000 - 2001: Postdoctoral fellow, Prof. R. Testi"s Lab, Dep. Experimental Medicine and Biochemical Sciences, University "Tor Vergata", Rome, Italy.
2001-2007: Group Leader, Assistant Telethon Scientist, Dulbecco Telethon Institute at Dep. of Exp. Medicine and Biochem. Sciences, University of "Tor Vergata, Rome, Italy.
2005-today: Group Leader, Cell Signaling Unit Fondazione Santa Lucia, Rome, Italy.
2008-today: Researcher (Genetics BIO/18), Department of Biology, University of Rome, Tor Vergata. Rome, Italy
Work Address: Department of Biology, University of Rome Tor Vergata
Fondazione Santa Lucia
Via del Fosso di Fiorano 64 - 00143 Rome, Italy
phone: 39-6-501703168
fax: 39-6-501703330
e-mail: daniela.barila@uniroma2.it
EDUCATION
1991: Degree with honours in Biological Sciences, University of Rome "La Sapienza"
1994: Specialization with honours in Biotechnology
POSTGRADUATE EDUCATION AND POSITION HELD
1991-1994: Specialization Fellow, National Institute for Nutrition (INRAN), Rome, Italy.
1993: Visiting fellow, Prof. T. Morimoto"s lab., Cell Biology Dep., New York University, NY, USA
1995-1999: Postdoctoral fellow, Dr. G. Superti Furga"s Lab, Cell Regulation Dep., European Molecular Biology Laboratory (E.M.B.L.), Heidelberg, Germany.
2000 - 2001: Postdoctoral fellow, Prof. R. Testi"s Lab, Dep. Experimental Medicine and Biochemical Sciences, University "Tor Vergata", Rome, Italy.
2001-2007: Group Leader, Assistant Telethon Scientist, Dulbecco Telethon Institute at Dep. of Exp. Medicine and Biochem. Sciences, University of "Tor Vergata, Rome, Italy.
2005-today: Group Leader, Cell Signaling Unit Fondazione Santa Lucia, Rome, Italy.
2008-today: Researcher (Genetics BIO/18), Department of Biology, University of Rome, Tor Vergata. Rome, Italy
We are interested in the elucidation of the signal transduction pathways dependent of phosphorylation through which cell homeostasis is ensured in normal and pathological conditions such as cancer. In particular we are currently focusing on three kinases, Src, c-Abl and ATM, and in the investigation of the signaling cascades through which these molecules modulate cell death, cell migration and cell transformation in cancer
Role of Caspase-8 phosphorylation on Tyr380
We have recently identified Tyr380 phosphorylation of Caspase-8 as a novel molecular mechanism through which Src family kinases modulate Caspase-8 function. Phosphorylation on Tyr380 impairs death receptor dependent apoptosis and positively modulates cell adhesion and migration. We are characterizing the role of this phosphorylation in cell transformation and in tumorigenesis in vitro and in vivo.
Role of ATM kinase in the modulation of protein stability and autophagy
We are investigating the molecular mechanisms through which ATM (Ataxia Telangiectasia Mutated) kinase modulates c-FLIP protein stability and death receptor induced apoptosis. Furthermore, we are testing the role of ATM genetic and pharmacological modulation in autophagy triggered by nutrient deprivation or oxidative stress.
Role of c-Abl and ATM kinases in Receptor Tyrosine Kinases (RTKs) dependent tumors.
We are interesting in improving the therapeutic targeting of RTKs dependent cancer cells, which are normally very resistant to classical chemotherapy and radiotherapy approaches. In particular we are evaluating the potential role of c-Abl and ATM kinases genetic and pharmacological targeting on cell survival, cell death stemness and senescence of Met and ErbB2 overexpressing cellular models. Our aim is to clarify the signalling cascades through which kinases modulate tumorigenecity and to address the potential value of their targeting in vitro and in vivo in combined
Role of Caspase-8 phosphorylation on Tyr380
We have recently identified Tyr380 phosphorylation of Caspase-8 as a novel molecular mechanism through which Src family kinases modulate Caspase-8 function. Phosphorylation on Tyr380 impairs death receptor dependent apoptosis and positively modulates cell adhesion and migration. We are characterizing the role of this phosphorylation in cell transformation and in tumorigenesis in vitro and in vivo.
Role of ATM kinase in the modulation of protein stability and autophagy
We are investigating the molecular mechanisms through which ATM (Ataxia Telangiectasia Mutated) kinase modulates c-FLIP protein stability and death receptor induced apoptosis. Furthermore, we are testing the role of ATM genetic and pharmacological modulation in autophagy triggered by nutrient deprivation or oxidative stress.
Role of c-Abl and ATM kinases in Receptor Tyrosine Kinases (RTKs) dependent tumors.
We are interesting in improving the therapeutic targeting of RTKs dependent cancer cells, which are normally very resistant to classical chemotherapy and radiotherapy approaches. In particular we are evaluating the potential role of c-Abl and ATM kinases genetic and pharmacological targeting on cell survival, cell death stemness and senescence of Met and ErbB2 overexpressing cellular models. Our aim is to clarify the signalling cascades through which kinases modulate tumorigenecity and to address the potential value of their targeting in vitro and in vivo in combined
Marzano, V, Santini, S, Rossi, C, Zucchelli, M, D'Alessandro, A, Marchetti, C, Mingardi, M, Stagni, V, Barilà, D and Urbani, A. (2012) Proteomic profiling of ATM kinase proficient and deficient cell lines upon blockage of proteasome activity. J Proteomics; 75: 4632-46
Stagni, V, Santini, S and Barilà, D. (2012) A New Player in the Development of TRAIL Based Therapies for Hepatocarcinoma Treatment: ATM Kinase. Cancers; 4: 354-378.
Mongiardi, MP, Stagni, V, Natoli, M, Giaccari, D, D'Agnano, I, Falchetti, ML, Barilà, D, Levi, A. (2011) Oxygen sensing is impaired in ATM-defective cells. Cell Cycle; 10: 4311-20.
Furlan, A, Stagni, V, Hussain, A, Richelme, S, Conti, F, Prodosmo, A, Destro, A, Roncalli, M, Barilà, D. and Maina F. (2011) Abl interconnects oncogenic Met and p53 core pathways in cancer cells. Cell Death Differ; 18: 1608-16.
Stagni, V., Mingardi, M., Santini, S., Giaccari,D. and Barilà D. (2010) ATM kinase activity modulates cFLIP protein levels: potential interplay between DNA damage signaling and TRAIL induced apoptosis. Carcinogenesis; 31: 1956-63.
Barbero, S., Mielgo, A., Torres, V., Teitz, T., Shields, D.J., Mikolon, D., Bogyo, M., Barilà D., Lahti, J.M., Schlaepfer, D. and Stupack, D. (2009) Caspase-8 association with focal adhesion complex promotes tumor cell migration and metastasis. Cancer Res 69: 3755-63.
Torres, VA., Mielgo, A., Barilà D, Anderson, DH. and Stupack D. (2008) Caspase 8 promotes peripheral localization and activation of rab5. J Biol Chem; 283: 36280-9.
Barbero, S., Barilà, D., Mielgo, A., Stagni, V.,Clair, K. and Stupack, D. (2008) Identification of a critical tyrosine residue in caspase 8 that promotes cell migration. J Biol Chem 283:13031-4.
Stagni, V., di Bari, M.G., Condò, I., Cursi, S., Testi, R. Cundari, E. and Barilà, D. (2008) ATM deficiency triggers resistance to Fas-induced apoptosis in lymphoid cells. Blood 111:829-37.
Podar, K., Raab, M.S., Tonon, G., Martin, S., Barilà, D., Zhang, J., Tai, Y-T., Yasui, H., Raje, N., DePinho, R.A., Hideshima, T., Chauhan, D. and Anderson, K.C. (2007) Upregulation of c-Jun inhibits proliferation and induces apoptosis via caspase-triggered c-Abl cleavage in human multiple myeloma. Cancer Research 67:1680-1688
di Bari, M.G., Ciuffini, L., Mingardi, M., Testi, R, Soddu, S. and Barilà, D. (2006) c-Abl acetylation by HATs regulates its nuclear-cytoplasmic localization. EMBO Reports 7: 727-733.
Cursi, S., Rufini, A., Stagni, V., Condò, I., Bachi, A., Paniccià Bonifazi, A., Coppola, L., Superti-Furga, G., Testi, R. and Barilà, D. (2006) Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression. EMBO Journal 25: 1895-1905.
Holcomb, M., Rufini, A., Barilà, D. and Klemke, R.L. (2005) Deregulation of proteosome function induces Abl-mediated cell death by uncoupling p130 CAS and C-CrkII. J Biol Chem 23: 2430-2440.
Barilà D, Rufini A, Condò I, Ventura N, Dorey K, Superti-Furga G and Testi R. (2003) Caspase-dependent cleavage of c-Abl contributes to apoptosis. Mol Cell Biol. 23: 2790-9.
Barilá D, Mangano R, Gonfloni S, Kretzschmar J, Moro M, Bohmann D, and Superti-Furga G. (2000) A nuclear tyrosine phosphorylation circuit: c-Jun a san activator and substrate of c-Abl and JNK. EMBO J 19: 273-81.
Barilá D and Superti-Furga G. (1998) An intramolecular interaction regulates c-Abl activity. Nat Genet. 18:280-2.
Stagni, V, Santini, S and Barilà, D. (2012) A New Player in the Development of TRAIL Based Therapies for Hepatocarcinoma Treatment: ATM Kinase. Cancers; 4: 354-378.
Mongiardi, MP, Stagni, V, Natoli, M, Giaccari, D, D'Agnano, I, Falchetti, ML, Barilà, D, Levi, A. (2011) Oxygen sensing is impaired in ATM-defective cells. Cell Cycle; 10: 4311-20.
Furlan, A, Stagni, V, Hussain, A, Richelme, S, Conti, F, Prodosmo, A, Destro, A, Roncalli, M, Barilà, D. and Maina F. (2011) Abl interconnects oncogenic Met and p53 core pathways in cancer cells. Cell Death Differ; 18: 1608-16.
Stagni, V., Mingardi, M., Santini, S., Giaccari,D. and Barilà D. (2010) ATM kinase activity modulates cFLIP protein levels: potential interplay between DNA damage signaling and TRAIL induced apoptosis. Carcinogenesis; 31: 1956-63.
Barbero, S., Mielgo, A., Torres, V., Teitz, T., Shields, D.J., Mikolon, D., Bogyo, M., Barilà D., Lahti, J.M., Schlaepfer, D. and Stupack, D. (2009) Caspase-8 association with focal adhesion complex promotes tumor cell migration and metastasis. Cancer Res 69: 3755-63.
Torres, VA., Mielgo, A., Barilà D, Anderson, DH. and Stupack D. (2008) Caspase 8 promotes peripheral localization and activation of rab5. J Biol Chem; 283: 36280-9.
Barbero, S., Barilà, D., Mielgo, A., Stagni, V.,Clair, K. and Stupack, D. (2008) Identification of a critical tyrosine residue in caspase 8 that promotes cell migration. J Biol Chem 283:13031-4.
Stagni, V., di Bari, M.G., Condò, I., Cursi, S., Testi, R. Cundari, E. and Barilà, D. (2008) ATM deficiency triggers resistance to Fas-induced apoptosis in lymphoid cells. Blood 111:829-37.
Podar, K., Raab, M.S., Tonon, G., Martin, S., Barilà, D., Zhang, J., Tai, Y-T., Yasui, H., Raje, N., DePinho, R.A., Hideshima, T., Chauhan, D. and Anderson, K.C. (2007) Upregulation of c-Jun inhibits proliferation and induces apoptosis via caspase-triggered c-Abl cleavage in human multiple myeloma. Cancer Research 67:1680-1688
di Bari, M.G., Ciuffini, L., Mingardi, M., Testi, R, Soddu, S. and Barilà, D. (2006) c-Abl acetylation by HATs regulates its nuclear-cytoplasmic localization. EMBO Reports 7: 727-733.
Cursi, S., Rufini, A., Stagni, V., Condò, I., Bachi, A., Paniccià Bonifazi, A., Coppola, L., Superti-Furga, G., Testi, R. and Barilà, D. (2006) Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression. EMBO Journal 25: 1895-1905.
Holcomb, M., Rufini, A., Barilà, D. and Klemke, R.L. (2005) Deregulation of proteosome function induces Abl-mediated cell death by uncoupling p130 CAS and C-CrkII. J Biol Chem 23: 2430-2440.
Barilà D, Rufini A, Condò I, Ventura N, Dorey K, Superti-Furga G and Testi R. (2003) Caspase-dependent cleavage of c-Abl contributes to apoptosis. Mol Cell Biol. 23: 2790-9.
Barilá D, Mangano R, Gonfloni S, Kretzschmar J, Moro M, Bohmann D, and Superti-Furga G. (2000) A nuclear tyrosine phosphorylation circuit: c-Jun a san activator and substrate of c-Abl and JNK. EMBO J 19: 273-81.
Barilá D and Superti-Furga G. (1998) An intramolecular interaction regulates c-Abl activity. Nat Genet. 18:280-2.
Project Title:
Role of ATM and c-Abl kinases in RTKs dependent tumorigenesis
The aim of this projec is to investigate the role of ATM kinase and c-Abl non receptor tyrosine kinase in RTKs dependent tumorigenesis. Several in vivo and in vitro experimental approaches will developed including in vitro transformation assay and mouese xenograft experiments using a panel of cell lines genetically silenced for ATM or c-Abl expression or not. The molecular mechanisms through which ATM and c-Abl may modulate tumorigenicity will be investigated. Inhibitors of the activity of these kinases will be also assayed in combination with chemoterapy or RTKs inhibitors to evaluate their therapeutic potential. Finally the activity of these kinases will be also verified in human cancer.