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Laboratory for Research of Apoptosis Mechanisms

Invited researcher Boris Davidovich Zhivotovskiy
Contract number
11.G34.31.0006
Time span of the project
2010-2012

As of 30.01.2020

15
Number of staff members
58
scientific publications
1
Objects of intellectual property
General information

Name of the project: Molecular mechanisms of apoptosis and their role in various pathologies

Strategy for Scientific and Technological Development Priority Level: в


Goals and objectives

Research directions: Role of inter nations between various mechanisms of cell death in tumor therapy

Project objective: Research of the role of interactions between various mechanisms of cell death in cancer therapy


The practical value of the study

  • We have observed spatiotemporal activation of caspase-2.
  • A new high-molecular complex of activation of caspase-2 has been determined that are different from PIDDosome.
  • The role of caspase-2 in necroptosis and programmed necrosis has been determined, caspase-2 affects negative regulation of necroptosis.
  • It has been determined that translocation of caspase-2 can play a certain role in switches from one type of death to another.
  • A range of kinases/phosphatases has been found in caspase-2 interactome (such as calmodulin kinase, 14-3-3 kinase, as well as РР1 phosphatase).
  • New proteins (RFXANK and FAN) have been found that are connected to caspase-2, pointing at non-apoptotic function of this protease.
  • We have shown that one of the most widespread types of caspase modification – along with phosphorylation – is ubiquitination.
  • We have shown that post-transcriptional phosphorylation of caspases is characterized by high conservatism, while analysis of spatial structure allowed to determine general laws in control of caspase activation by phosphorylation.
  • The laboratory has studied the mechanism and consequences of permeabilization of outer mitochondrial membrane in terms of properties of proteins that are parts of cytoplasm.
  • We have studied impact of antitumor medications on hemostasis of calcium in ells of neuroblastoma with various levels of MycN expression.
  • The role of active forms of oxygen in permeabilization of outer mitochondrial membrane has been confirmed.
  • We have analyzed of apoptosis signaling pathways regulated by microRNA in cells of non-small-cell lung cancer and attempted to modify the using external impacts.
  • Our researchers have determined the role of proteins of the Bcl-2 family in regulating mitotic catastrophe and in switching between various modes of cell death.
  • We have shown that accumulation of active forms of oxygen in volume insufficient to launch cell death initiates a mitotic catastrophe.
  • It has been determined that suppression of autophagy can lead to deceleration of cell proliferation in non-small-cell lung cancer and increase of their sensitivity to cisplatin induced caspase-dependent and caspase-independent apoptosis by stimulation of active forms of oxygen formation.
  • It has been determined that deficit of mitochondria leads to increased sensitivity to mitotic catastrophe determined by morphological criteria.
  • We have proposed and confirmed a hypotesis that in the presence of developing cell stress after inducing a mitotic catastrophe further instability of genome serves as an «amplification loop» for development of mitotic catastrophe and provokes initiations of either autophagy or mitophagy.
  • Our Laboratory has shown that development of mitotic catastrophe activates both autophagy and apoptosis. Mitoti catastrophe and autophagy can mutually regulate each other.
  • We have shown that the type of cell death in the state of mitotic catastrophe depends on insensitivity of the mitotic catastrophe, presence of the 14-3-3σ protein and mitochondrial proteins of Bcl-2: Bcl-xL, and Mcl-1 families.
  • It has been determined that the role of the TSN protein in regulating RNA interference machinery is not important for development of immunity to сisplatin in adenocarcinome cells, and the described effect is caused by mediation of transcription by the TSN function.
  • We have determined a series of events including a sequence of functions of three proteins TSN-S100A11-cPLA2 that influences response of non-small-cell lung cancer cells to chemotherapy.
  • Our search has shown absence of significant contribution of autophagy to strengthening of cisplatin-induced cell death in the context of limited nutrients.
  • The role of the Mcl-1 protein in cell death under serum deprivation has been determined. 
  • We have shown that accumulation of damaged mitochondria in cells with autophagy deficit can lead to activation of apoptotic response under various stressful circumstances including starvation.
  • It has been determined that the mechanism of action of cardiac glycosides is caused by activity of calcium ions as secondary messengers and by ability of calcium to inhibit topoisomerase II that is the target for etoposide which leads to significant damage of RNA and death of tumor cells.
  • Our researchers have reviewed P-gp glycoprotein as the target for stimulating therapeutic activity of mediation that will assist effective elimination of tumor cells when using therapeutic concentrations of antitumor medications.

Education and career development:

  • We have organized the «Programmed cell death in biology and medicine» international conference (Russia, 2012).
  • We have organized the international conference of the European Cell Death Organization (ECDO) «Cell death during diseases: from minor molecules to translational medicine» (Russia, 2018).
  • 4 candidate dissertations, 13 masters dissertations.
  • We have conducted courses for students and young professionals: «Programmed cell death: theory and practice», «Programmed cell death in biology and medicine», «Programmed cell death», «Programmed cell death» (in English), «Toxicology in medicine» (in English), «Molecular programming of human cells».

Organizational and structural changes:

For professionals from Moscow and other Russian cities the Laboratory serves as a base center for consulting in cell death mechanisms research.

Other results:

  • We have received 4 grants from the Russian Science Foundation, 11 grants from the Russian Foundation for Basic Research, 1 grant from the «Dinastiya» foundation, 2 grants for young scientists from the President of Russia and 1 grant for support of scientific schools from the President of Russia.
  • 23 awards have been received at scientific contests
  • Patent for «A method to isolate protein highly molecular complex of caspase-2 activation in humans» was obtained in 2018.

Collaborations:

Karolinska Institute (Sweden), Otto von Guericke University Magdeburg(Germany): joint research of various aspects of cell death, joint publications, scientific internships

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Zamaraev A.V., Kopeina G.S., Prokhorova E.A., Zhivotovsky B., and Lavrik I.N
Post-translational Modification of Caspases: the Other Side of Apoptosis Regulation. Trends in Cell Biology 27(5): 322–339 (2017).
Senichkin V.V., Kopeina G.S., Prokhorova E.A., Zamaraev A.V., Lavrik I.N., and Zhivotovsky B.
Modulation of Mcl-1 Transcription by Serum Deprivation Sensitizes Cancer Cells to Cisplatin. Biochimica et Biophysica Acta (BBA) 1862(3): 557–566 (2018).
Sorokina I.V., Denisenko T.V., Imreh G., Tyurin-Kuzmin P.A., Kaminskyy V.O., Gogvadze V., and Zhivotovsky B.
Involvement of Autophagy in the Outcome of Mitotic Catastrophe. Scientific Reports 7(1): 14571 (2017).
Denisenko T.V., Sorokina I.V., Gogvadze V., and Zhivotovsky B.
Mitotic Catastrophe and Cancer Drug Resistance: A Link that Must to be Broken. Drug Resistance Updates 24: 1–12 (2016).
Kaminskyy V.O., Piskunova T., Zborovskaya I.B., Tchevkina E.M., and Zhivotovsky B.
Suppression of Basal Autophagy Reduces Lung Cancer Cell Proliferation and Enhances Caspase-dependent and –independent Apoptosis by Stimulating ROS formation. Autophagy 8(7): 1032–1044. (2012).
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