Girardini, Javier
GROUP LEADER NAME (as it appears in publications):
Girardini Javier E.
AFFILIATION:
Insituto de Biología Molecular y Celular de Rosario. IBR-CONICET. Argentina.
TEL:*
+54 341 4237070 ext 651/615
FAX:*
+54 341 4390465
EMAIL:*
girardini@ibr-conicet.gov.ar
WEB:
http://www.ibr-conicet.gov.ar/laboratorio/oncologia-molecular/
GROUP NAME / RESEARCH INTEREST IN FEW WORDS:
Molecular Oncology / Molecular bases of tumor aggressiveness. Zebrafish models for cancer research
SHORT SUMMARY OF RESEARCH INTEREST (MAX. 200 WORDS):
Note: please attach at the end of the form a longer description, with a maximum of 2000 words.
The main interest of our lab is the characterization of the molecular bases of cancer, with special emphasis on tumor aggressiveness. In the vast majority of cancers lethality is associated to the development of metastasis. Therefore, understanding the mechanisms that allow tumors cells to leave the primary tumor and colonize the organism is critical. A prominent role in this process is played by signalling pathways which become entangled in oncogenic circuits that reprogrammes tumor cell behaviour. We are interested in understanding how these circuits may promote the acquisition of aggressive tumor phenotypes. In particular, we are studying the biological consequences of altered prolil-directed phosphorylation signalling and how this may impinge on other cancer related alterations. We believe that zebrafish may provide unique tools to answer unresolved issues in cancer biology that are difficult to study using other experimental models.
LIST OF UP TO FIVE RELEVANT PUBLICATIONS:
1-“Disarming mutant p53 oncogenic function” Girardini JE, Marotta C, Del Sal G. Pharmacol Res. 2013. Nov 15 (79C): 75-87. doi: 10.1016/j.phrs. 2013.11.003. [Epub ahead of print].
2-“A Pin1/Mutant p53 Axis Promotes Aggressiveness in Breast Cancer” J.E. Girardini, M. Napoli, S. Piazza, A. Rustighi, C. Marotta, E. Radaelli, V. Capaci, L. Jordan, P. Quinlan, A. Thompson, M. Mano, A. Rosato, T. Crook, E. Scanziani, A.R. Means, G. Lozano, C. Schneider, and G. Del Sal. Cancer Cell. 20:79-91. 2011.
GROUP MEMBERS (NAME, POSITION, EMAIL):*
1- Solange Ibarra, Ph.D. student, ibarra@ibr-conicet.gov.ar
2- Carla Borini, Ph.D. student, borini@ibr-conicet.gov.ar
3- Carolina Rossi, Undergraduate student
FISH FACILITIES (TYPE OF FISH SYSTEM/TANKS, CAPACITY, ETC.)*
IBR zebrafish Facility: The fish system consist of 45 tanks, with a total volume of 1.500 l, and capacity for 500 fish. Filtered water is produced in the facility (200 l / day). Fish are kept under controled conditions (28 °C, light/dark cycle).
FISH LINES KEPT IN STOCK:*
OTHER EQUIPMENT RELATED TO ZEBRAFISH RESEARCH*
Microinjector, micromanipulator. microscopes
LAB EXPERTISE AND TECHNICAL CAPABILITIES (RELATED TO ZEBRAFISH RESEARCH)*
Microinjection, transient and stable genetic manipulation (DNA injection), morpholino knock down, gene expression analysis ( in situ hybridization, qPCR, immunofluorescence, western blot), confocal microscopy, DNA cloning and molecular biology techniques.
Research interest
Phophorylation signalling plays a prominent role in the regulation of cell behaviour. Among them, modification of Ser-Pro or Thr-Pro motifs (S/T-P motifs), known as prolil-directed phosphorylation, is a well conserved mechanism involving several protein kinases. A key role in this signal transduction mechanism is played by the prolil isomerase Pin1, which binds to phosphorylated S/T-P motifs in protein substrates and modifies their function by inducing local conformational changes. The ability to act on several different protein substrates allows Pin1 to act as a global modulator of cell signalling able to radically change the response to a combination of stimuli. Abnormally high Pin1 levels may contribute with tumor progression by different mechanisms that perturb cell signalling. To deal with the daunting complexity of oncogenic signalling we are using zebrafish embryos as biosensors able to unveil the action of signals arising from oncogenic lesions in vivo. Studying alterations in embryogenesis we are trying to understand which signalling pathways and which cell types may be affected by Pin1 misfunction.
A particularly deleterious connection in oncogenic signaling circuitry is the cooperation between Pin1 and p53 point mutants. Missense mutations on the p53 gene are frequently found in human tumors and as a consequence p53 point mutants acquire new functions that subvert an efficient tumor suppressor pathway into a mechanism of tumor aggressiveness that promotes the development of metastasis. Through binding and amplification of mutant p53 oncogenic function, Pin1 and mutant p53 establish a molecular axis that links oncogenic signalling with downstream mechanisms of aggressiveness. We are working on the characterization of the molecular mechanisms underlying this cooperation focusing on the ability of mutant p53 to alter gene expression. We are also generating transgenic fish which will provide novel in vivo models for cancer research. The ability of Pin1 to act simultaneously on several different substrates makes it an ideal candidate for therapy design, since manipulation of Pin1 activity may contribute to amplify the response elicited by pharmacologic agents. In our lab we are studying the potential of Pin1 inhibition to be applied in combined therapies for cancer treatment.