Giannino Del Sal
Giannino Del Sal
affiliation: LNCIB - Laboratorio Nazionale CIB, Trieste
research area(s): Cancer Biology, Cell Biology
Course: Molecular Biomedicine
University/Istitution: Università di Trieste

Since 2001: Full professor of Cell Biology, Faculty of Medicine, University of Trieste.
Since 2006: Director of the PhD School in Molecular Biomedicine, University of Trieste.
Since 1997: Chief of Molecular Oncology Unit, Laboratorio Nazionale CIB, Area Science Park, Trieste.
1998 - 2001: Associate professor of Cell Biology, Faculty of Medicine, University of Trieste.
1994 - 1996: Visiting scientist, Department of Cell Biology Mitotix Inc., Cambridge (MA), USA.
1992 - 1998: University researcher, Faculty of Medicine, University of Trieste and Laboratorio Nazionale CIB, Area Science Park, Trieste.
1989 - 1991: Associate expert, International Center for Genetic and Biotechnology (ICGEB), Trieste.
1988: AIRC fellow, International Center for Genetic Engineering and Biotechnology (ICGEB), Trieste.
1987: AIRC fellow, European Molecular Biology Laboratory (EMBL) Heidelberg - Germany.
1985 - 1986: Research fellow, University of Trieste.
1984: Degree in Biological Sciences, University of Trieste.
Our group is involved in both basic and traslational research in the field of molecular oncology. All our research interests are essentially focused on signalling pathways relevant in cancer and in particular on the tumor suppressor p53 and its neighbourhood.

A vast body of evidence from clinical and basic research studies has demonstrated that this protein and its signal transduction pathway act as an essential barrier in preventing cancer onset and development. Thus the p53 pathway represents an essential cellular net protecting cells from malignant transformation.

Somatic mutations of p53 have been reported in more than 50% of all human cancers, the majority being missense mutations that lead to the expression of full-length mutant proteins. Several lines of evidence have established that a subset of p53 mutants gain new oncogenic functions and concur to development of invasive and metastatic phenotypes.

Also in tumors expressing the wild-type protein, the p53 pathway may be inactivated through indirect mechanisms, involving deregulated expression of p53 inhibitors, such as MDM2 or iASPP, or loss of coactivators.

Although having been the object of extensive studies, the p53 pathway retains a number of aspects that still need to be elucidated. Many signaling pathways cross the p53 network as a consequence of different stress stimuli. But what events control its decision to activate senescence or apoptosis rather than DNA repair? What are the bases of the gain of function properties of mutant p53? Which modifications and protein complexes are responsible for its aberrant activities? These are only a few examples of the still open question in this field.

Over the years we have contributed significantly to expand our understanding of the regulation and disregulation of the p53 pathway. We have characterised new post-translational modifications and new sub-cellular localization of p53 and unveiled the essential role of its phosphorylation-dependent conformational changes, that are required for protein stabilization and activation upon DNA damage. We have identified novel cofactors able to modulate p53 mediated responses (e.g. apoptosis and senescence) and its family members' functions . We have revealed the stringent dependance of p53, either the wild type or the mutant protein, from the prolyl isomerase Pin1 in exerting either the tumor suppressive or the oncogenic functions. Recently, our work has demonstrated the existence in tumor cells of a Pin1/mutant p53 molecular axis which fuel tumor aggressiveness and invasive behaviour. In particular we have identified a Pin1/mutant p53 molecular signature which presents a strong prognostic value in breast cancer. For the enzyme Pin1, we have also identified a critical role in regulating another key protein in cancer, Notch1. Moreover we have isolated small aptamers able to bind specifically mutant p53, thus interfering with its oncogenic function in tumor cells.

By means of a combination of biochemical, molecular genetics and cell biology approaches and of mouse tumor models, our research now aims at exploring other levels of complexity regarding both the p53 and the mutant p53 pathways and their impact on tumor trasformation, progression and metastasis, investigating the role of Pin1 in modulating the cytoplasmic functions of p53, searching for and characterizing novel cofactors and miRNAs regulating these signalling pathways, as well as miRNAs that are targets of mutant p53.
We are also interested in deepening our understanding of the Pin1/Notch1 connection and of its role in tumorigenesis.
Another fundamental aspect of our research is the translation of our results into useful knowledge and tools for the clinical practice. In this regard we are focused on validating cancer-specific signatures emerging from our studies as novel predictive/therapeutic tools and on developing new therapeutic strategies.
1. Marcucci R, Brindle J, Paro S, Casadio A, Hempel S, Morrice N, Bisso A, Keegan LP, Del Sal G, O'Connell M. (2011). Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. EMBO J. In press.

2. Girardini JE, Napoli M, Piazza S, Rustighi A, Marotta C, Radaelli E, Capaci V, Jordan L, Quinlan P, Thompson A, Mano M, Rosato A, Crook T, Scanziani E, Means AR, Lozano G, Schneider C, Del Sal G. (2011). A Pin1/Mutant p53 Axis Promotes Aggressiveness in Breast Cancer. Cancer Cell. 20(1):79-91.

3. Bisso A, Collavin L, Del Sal G. p73 as a pharmaceutical target for cancer therapy. (2011). Curr Pharm Des. 17(6):578-90.

4. Collavin L, Lunardi A, Del Sal G. (2010). p53-family proteins and their regulators: hubs and spokes in tumor suppression. Cell Death Differ. 17(6):901-11.

5. Drost J, Mantovani F, Tocco F, Elkon R, Comel A, Holstege H, Kerkhoven R, Jonkers J, Voorhoeve PM, Agami R, Del Sal G. (2010). BRD7 is a candidate tumour suppressor gene required for p53 function. Nat Cell Biol. 12(4):380-9.

6. Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4+ T lymphocytes. Manganaro L, Lusic M, Gutierrez MI, Cereseto A, Del Sal G, Giacca M. (2010). Nat Med. 16(3):329-33.

7. Rustighi A, Tiberi L, Soldano A, Napoli M, Nuciforo P, Rosato A, Kaplan F, Capobianco A, Pece S, Di Fiore PP, Del Sal G. (2009). The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nat Cell Biol. 11(2):133-42.

8. Guida E, Bisso A, Fenollar-Ferrer C, Napoli M, Anselmi C, Girardini JE, Carloni P, Del Sal G. (2008). Peptide aptamers targeting mutant p53 induce apoptosis in tumor cells. Cancer Res. 68(16):6550-8.

9. Mantovani F, Tocco F, Girardini J, Smith P, Gasco M, Lu X, Crook T, Del Sal G. (2007). The prolyl isomerase Pin1 orchestrates p53 acetylation and dissociation from the apoptosis inhibitor iASPP. Nat Struct Mol Biol. 14(10):912-20.

10. Pinton P, Rimessi A, Marchi S, Orsini F, Migliaccio E, Giorgio M, Contursi C, Minucci S, Mantovani F, Wieckowski MR, Del Sal G, Pelicci PG, Rizzuto R. (2007). Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science. 315(5812):659-63.
No projects are available to students for the current accademic year.