Keywords: thyroid, brain, lung

In our laboratory we study the activity of the transcription factor, previously identified by us, called TTF-1/Nkx2.1. This factor is expressed in three cell types: the follicular cells of the thyroid, the epithelial cells of the lung, the neurons of the ventral part of the brain. During embryogenesis, TTF-1 plays a crucial role for the correct development of all three organs and its expression is also maintained in adults. Mutations in the gene coding for TTF-1 are associated with Benign Hereditary Chorea (BHC), Hypothyroidism and Respiratory Distress. These three pathologies are brought together in the syndrome called Brain-Thyroid-Lung syndrome. Our project involves the study of the role of TTF-1 in all three districts and for all three diseases associated with its activity. In the thyrocyte we study how TTF-1 interacts with other thyroid-specific transcription factors (TTF-2 / FoxE1 and Pax8) in the regulation of thyroid homeostasis. In the lung, we study the role of TTF-1 in lung cancer. In the neurons involved with BHC we want to identify the target genes of TTF-1.

Education

Date of Birth: 4th-Oct-1955

Position: Researcher (permanent position), National Council Research (CNR), Italy

EDUCATION:
1974: High school certificate at “P. Albertelli” Gymnasium, Rome
1975-1980: La Sapienza, Universuty of Rome- Doctoral Degree in Biology

RESEARCH ACTIVITY
1980-1982: La Sapienza, University of Rome- Post-graduate Fellow in prof. G. Morpurgo’s lab.
1982-1986: Institute of Cell Biology, CNR, Rome- CNR Fellow in prof. Tocchini-Valentini’s lab.
1986-1990: EMBL, Heidelberg, Germany- Visiting scientist in prof. Di Lauro’s laboratory.
1990-1991: Staff member in the Institute of Cell Biology, CNR, Rome and Visiting scientist at Biochemistry and Molecular Biology, Department, University of Chicago, Chicago, USA
1991-1995: Consorzio M. Negri Sud, S. Maria Imbaro, Chieti- Visiting scientist as Group leader
1995-2001: Regina Elena Cancer Institute, Rome- Visiting scientist as Group leader
2001-2019: Institute of Cell Biology and Neurobiology, CNR, Rome as Staff Researcher.
2014-2017: Institute of Biomedical Sciences, University of São Paulo, Brazil. Visiting scientist
2019-present: Institute of Biochemistry and Cell Biology, CNR, Monterotondo (Rome). Staff Researcher

Assignments:

2013. Winner of “Ciencia sem fronteira” Chamada de Projetos nº 71/2013 – Pesquisador Visitante Especial (2014-2017). Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES (Ministério da Educação) Brazil.

2006- 2012 Head of the section “Hormonogenesis and thyroid differentiation” (commessa CNR ME.P05.008)

2007– Appointee by the CNR as expert in the IFO/CNR agreement on “Metabolomic studies in human pathologies” (prot. N.456 26/01/2007).

• Provenzano C, Veneziano L, Appleton R, Frontali M, Civitareale D. Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea. Journal of Neurological Sciences, 264(1-2), 56-62, 2008.
• Stefania Miccadei, Barbara Pascucci, Mauro Picardo, Pier Giorgio Natali and Donato Civitareale. Identification of the minimal melanocyte-specific promoter in the melanocortin receptor 1 gene. Journal of Experimental & Clinical Cancer Research, 27, 71-79, 2008
• Provenzano C, Pascucci B, Lupari E and Civitareale D. Large scale analysis of transcription factor TTF-1/NKX2.1 target genes in GnRH secreting cell line GT1-7. Molecular and Cellular Endocrinology, 323, 215-223, 2010.
• Claudia Provenzano, Michela Zamboni, Liana Veneziano , Elide Mantuano, Barbara Garavaglia, Giovanna Zorzi, Javier Pagonabarraga, Paola Giunti and Donato Civitareale. Functional characterization of two novel mutations in TTF-1/Nkx2.1 homeodomain in patients with Benign Hereditary Chorea. Journal Neurological Sciences. 2016;360:78-83
• Michela Zamboni and Donato Civitareale, TTF-1/Nkx2.1 functional connection with mutated EGFR relies on LRIG1 and β-catenin pathways in lung cancer cells. Biochem Biophys Res Commun. 2018;505(4):1027-1031.

1-F. Pacchierotti, D. Bellincampi and D. Civitareale, Cytogenetic observations, in mouse secondary spermatocytes, on numerical and structural chromosome aberrations induced by cyclophosphamide in various stages of spermatogenesis. Mutation Research 119, 177-183, 1983

2-D. Civitareale, L. Ghibelli and R. Di Lauro, Partial purification of a nuclear protein recognising the rat thyroglobulin promoter. Hormone and Metabolic Research S17, 73-77, 1987

3-D. Civitareale, R. Lonigro, A.J. Sinclair and R. Di Lauro, A thyroid-specific nuclear protein essential for tissue-specific expression of the thyroglobulin promoter. EMBO Journal, 8, 2537-2542, 1989

4- A.J. Sinclair, R. Lonigro, D. Civitareale and R. Di Lauro, Thyroid-specific gene expression. In Control of Thyroid Gland. R. Ekhom. L. D. Kohon and S. Wollman eds., Plenum Publishing Corporation, 373-389, 1989.

5- A.J. Sinclair, R. Lonigro, D. Civitareale, L. Ghibelli and R. Di Lauro, The tissue-specific expression of the thyroglobulin gene requires complex interaction between thyroid-specific and ubiquitous factors. Eur. J. Biochemistry, 193, 311-318, 1990

6-D. Civitareale, P. Castelli, P. Falasca, A. Saiardi, The thyroid transcription Factor 1 activates the promoter of the thyrotropin receptor gene. Molecular Endocrinology, 7, 1589-1593, 1993

7-G. Damante, D. Fabbro, L. Pellizzari, D. Civitareale, S. Guazzi, M. Polycarpou-Schwarz, S. Cauci, F. Quadrifoglio, S. Formisano, R. Di Lauro, Sequenze-specific DNA recognition by TTF-1HD. Nucleic Acid Research, 22, 3075-3083, 1994.

8-D. Civitareale, A. Saiardi, P. Falasca, Purification and characterization of thyroid transcription factor 2, The Biochemical Journal, 304, 981-985, 1994

9- A. Saiardi, P. Falasca and D. Civitareale, The thyroid hormone inhibits the thyrotropin receptor promoter activity. Evidence for a short loop regulation. Biochemical and Biophysical Research Communication, 205, 230-235, 1994.

10-A. Saiardi, V. Tassi, V. De Filippis and D. Civitareale, Cloning and sequencing of the human Thyroid Transcription Factor 1. Biophysical and Biochemical Acta, GSE, 1261, 307-310, 1995.

11-A. Saiardi, Falasca P. and D. Civitareale, Synergistic tramscriptional activation of the thyrotropin receptor promoter by CREB and TTF-1. The Biochemical Journal, 310, 491-496, 1995.

12-M. G. Perna, D. Civitareale, V. De Filippis, M. Sacco, C. Costernino, V. Tassi, Absence of mutation in the gene encoding Thyroid Transcription Factor 1 (TTF-1) in Patients with Thyroid Dysgenesis. Thyroid 7, 337-381, 1997

13-C. Esposito, S. Miccadei, A. Saiardi and D. Civitareale, Pax 8 activates the enhancer of the human thyroperoxidase gene. The Biochemical Journal, 331, 37-40, 1998

14-R. De Leo, S. Miccadei, E. Zammarchi and D. Civitareale, Role for p300 in Pax 8 induction of thyroperoxidase gene expression. Journal of Biological Chemistry, 275, 34100-34105, 2000

15- S. Miccadei, R. De Leo, E. Zammarchi and D. Civitareale, TTF-1 and Pax 8 cooperatively regulate the thyroid-specific gene expression of Thyroperoxidase and Thyroglobulin. Molecular Endocrinology, 16, 837-846, 2002

16- Miccadei S, Provenzano C, Mojzisek M, Natali PG, Civitareale D. Retinoblastome protein acts as Pax 8 transcriptional coattivator. Oncogene 24(47):6993-7001, 2005

17-Provenzano C, Veneziano L, Appleton R, Frontali M, Civitareale D. Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea. Journal of Neurological Sciences, 264(1-2), 56-62, 2008.

18.- Stefania Miccadei, Barbara Pascucci, Mauro Picardo, Pier Giorgio Natali and Donato Civitareale. Identification of the minimal melanocyte-specific promoter in the melanocortin receptor 1 gene. Journal of Experimental & Clinical Cancer Research, 27, 71-79, 2008

19.- Provenzano C, Pascucci B, Lupari E and Civitareale D. Large scale analysis of transcription factor TTF-1/NKX2.1 target genes in GnRH secreting cell line GT1-7. Molecular and Cellular Endocrinology, 323, 215-223, 2010.

20- Claudia Provenzano, Michela Zamboni, Liana Veneziano , Elide Mantuano, Barbara Garavaglia, Giovanna Zorzi, Javier Pagonabarraga, Paola Giunti and Donato Civitareale. Functional characterization of two novel mutations in TTF-1/Nkx2.1 homeodomain in patients with Benign Hereditary Chorea. Journal Neurological Sciences. 2016;360:78-83

21- Michela Zamboni and Donato Civitareale, TTF-1/Nkx2.1 functional connection with mutated EGFR relies on LRIG1 and β-catenin pathways in lung cancer cells. Biochem Biophys Res Commun. 2018;505(4):1027-1031.

Dr. Michela Zamboni (staff researcher IBBC-CNR)

Dr. Donato Civitareale (staff researcher IBBC-CNR)

Grants: 

1) Grant from the Italian Cancer Research Association (AIRC) “Role of the transcription factor TTF-2 in Thyroid tumors” (1992-1994)

2) Italian Telethon Grant N: E.254 “Molecular study of congenital hypothyroidism” (1995).

3) Grant from the Italian Space Agency “Role of gravity on thyroid-specific gene expression”(N° I/R/303/02, PG.ASI004163) (2002) .

4) FIRB 2001 N. RBAU019HHA from Italian Ministry of Research “Genome wide analysis of the TTF-1 target genes in the onset of sexual maturity” (2002-2005).

5) Grant from Italian Ministry of Research with IFO/San Gallicano Hospital , “Redox and melanoma” (IFO prot. N. 3128.) (2003-2004).

6) Grant from the Italian Space Agency (In the “Mo.Ma”. project with University of Udine. Prot. N° 44 TitIII cl 13-Fasc. 2). “Effects of gravity on tissue-specific gene expression and differentiation”. (2007-2012).