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Invited researcher Mauro Piacentini
Contract number
14.W03.31.0029
Time span of the project
2018-2020

As of 30.01.2020

19
Number of staff members
27
scientific publications
General information

Name of the project: Transglutaminase-2 ferment as a target for therapy of hepatocellular carcinoma

Strategy for Scientific and Technological Development Priority Level: в


Goals and objectives

Research directions: Identifying molecular mechanisms of oncogenesis and search for new targets for anti-tumor therapy

Project objective: Studying the role of transglutaminase-2 (TG2) and heat shock factor (HSF1) in the process of development of hepatocellular carcinoma in cells of model animals as well as assessment of prospects of the TG2/HSF1 path as a potential target for innovative therapy of hepatocarcinoma.


The practical value of the study

  • We have found the role of TG2 in regulation of reaction to stress through HSF1. HSF1 is is the main transcription factor controlling transcription of many genes reacting to stress including thermal heat proteins and thus regulates reaction of cells to proteotoxic stress. We have shown that loss of TG2 function correlates to disruption of HSF1 translocation into nucleus and its binding capability – to promotor of heat shock protein HSP70 70 kDa.
  • Our Laboratory has shown necessity of disulfide activity of TG2 for activation of stress reaction.
  • We have shown that formation of three intermolecular S-S links between two remnants of cystein in positions 36 and 103 (Cys36 and Cys103) is critically important for HSF1 trimerization and DNA binding. However the mechanism that helps Cys36 and Cys103 to form intermolecular S-S link has not yet been found out. We have shown that it is exactly disulfide isomerase activity and not transamidation activity of TG2 protein that is necessary for trimerization and activation of HSF1.
  • The effect of pharmacological inhibition of TG2 by сystamine has been proven.
  • By computer docking analysis we have shown that cysteamine can interact with TG2 near its active site inhibiting its transamidation and disulfide isomerase activity. We have shown that cysteamine blocks nuclear translocation and nuclear transcription of HSF1.
  • We have shown participation of TG2 in development of non-alcoholic fatty liver disease. We have demonstrated that absence of TG2 causes disruption of autophagy/mitophagy and leads to development of non-alcoholic fatty liver disease. The data has been obtained by analysis of human liver samples from patients with non-alcoholic fatty liver disease. as well as from studying mice models with TG2 knockout on a high fat diet.

Education and career development: 4 postgraduates of the Institute of Cytology and 4 students of the Saint Petersburg State University are working on their candidate dissertations at the Laboratory

Organizational and structural changes: We have started organizing a vivarium for keeping immunodeficient animals

Collaborations: University of Rome Tor Vergata (Italy): joint research and publications 

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Piacentini M., Baiocchini A., Del Nonno F., Melino G., Barlev N.A., Rossin F., D’Eletto M., Falasca L.
Non-Alcoholic Fatty Liver Disease Severity is Modulated by Transglutaminase Type 2. Cell Death & Disease 9(3): 257 (2018).
D’Eletto M., Rossin F., Fedorova O., Farrace M.G., Piacentini M.
Transglutaminase type 2 in the regulation of proteostasis. Biological Chemistry 400(2) (2018).
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