Prof. Malca[Malca Armon] Cohen-Armon

Associate Professor, Dept. of Physiology & Pharmacology, Sackler Faculty of Medicine, Tel Aviv University

Researcher, Neufeld Cardiac Research Institute
 

PARP Proteins in Health and Disease

The general focus of our research is on signal transduction mechanisms implicating PARP (polyADP-ribose polymerase) proteins. PARPs are
highly conserved proteins that are involved in a variety of processes, including epigenetic mechanisms, DNA repair, cell cycle and gene expression. PARP-
1, the most abundant PARP protein, is activated by binding to single strand DNA breaks. Activated PARP-1 recruits ligazes to the lesion, promoting
DNA repair.

One of our contributions to this field was the discovery of alternative mechanisms activating PARP-1 in the absence of DNA breaks. This unveiled a variety of extra-nuclear signals activating PARP proteins in a variety of processes regulating gene expression. We found that PARP-1 is a target of signal transduction mechanisms activated by intracellular Ca2+ mobilizition or by the MEK-ERK phosphorylation cascade. Moreover, we found that ERK activity in the nucleus is highly up-regulated by activated PARP-1, implicating PARP-1 in ERK-dependent gene expression. Up-regulation of immediate early genes underlying long-term memory formation may underlie the pivotal role of PARP-1 in long-term memory formation during learning. Regulation of gene expression, controlling cell growth and development, may underlie the role of PARP-1 in neuronal remodeling and cardiomyocytes growth.

Recently, we found that a phenanthrene derived PARP inhibitor acts as an extra-centrosomes de-clustering agent, exclusively and efficiently eradicating human cancer cells by ‘mitotic catastrophe’ cell death, without impairing normal cells. Since many human cancer cells depend on extra-centrosomes clustering for their survival, this molecule is now used for developing a novel cancer targeting therapy.

Geistrikh I., Visochek L., Klein R., Miller L., Mittelman L., Shainberg A. and Cohen-Armon M. 2011. Ca2+ induced PARP-1 activation and ANF expression are coupled events in cardiomyocytes. Biochem J. 438: 337–347.

Castiel A., Visochek L., Mittelman L., Dantzer F., Izraeli S., and Cohen-Armon M. 2011. A phenanthrene derived PARP inhibitor is an extra-centrosomes
de-clustering agent exclusively eradicating human cancer cells. BMC Cancer 11:412

Inbar D, Cohen-Armon M, Neumann D. 2012. Erythropoietin-driven signalling and cell migration mediated by polyADP-ribosylation. Br J Cancer.
107:1317-26

Castiel A, Visochek L, Mittelman L, Zilberstein Y, Dantzer F, Izraeli S, Cohen-Armon M. 2013. Cell death associated with abnormal mitosis observed
by confocal imaging in live cancer cells. J Vis Exp. (JOVE) 78:e50568.

Patents

• ‘Cancer Therapy’. US 8,729,080 B2
• ‘Treatment of Addiction’. US 13,761,761 B1