Tamar Kleinberger, PhD
Associate Professor of Microbiology
PhD, 1988 - Weizmann Institute, Israel
Induction of cancer-specific cell death and inhibition of DNA damage signaling by the adenovirus E4orf4 protein
The adenovirus E4orf4 protein is a multifunctional viral regulator. Within the context of the virus, E4orf4 contributes to temporal regulation of the progression of viral infection. When expressed alone, E4orf4 induces non-classical, caspase-independent cell death, which is more efficient in cancer cells than in normal cells, raising the possibility that study of E4orf4 signaling may have implications for cancer therapy. Notably, at least part of the E4orf4 signaling network is highly conserved in evolution from yeast to mammalian cells, underscoring its importance to cell regulation. Our recent studies revealed that interactions of E4orf4 with protein phosphatase 2A and with the ACF chromatin remodeling factor are important to E4orf4-induced cell death. Furthermore, E4orf4 inhibits cellular DNA damage signaling, as part of the battle between adenovirus and cellular antiviral defense mechanisms. Inhibition of the DNA damage response may underlie, at least in part, the cancer-specificity of E4orf4-induced cell death, as many cancers are deficient in damage signaling and thus may be more susceptible to inhibition of the remaining intact damage signaling pathways. Current research in the lab focuses on the interactions between E4orf4 and its partners, including chromatin proteins, and analysis of the interaction between E4orf4 and the host DNA damage response network.
Kleinberger T. 2015. Mechanisms of cancer cell killing by the adenovirus E4orf4 protein. Viruses. 7, 2334-2357.
Avital-Shacham M, Sharf R, and Kleinberger T. 2014. NTPDASE4 gene products cooperate with the adenovirus E4orf4 protein through PP2A-dependent and –independent mechanisms and contribute to induction of cell death. 2014. J Virol. 2014 88, 6318-28.
Pechkovsky A, Lahav M, Bitman E, Salzberg A, and Kleinberger T. 2013. E4orf4 induces PP2A- and Src-dependent cell-death in Drosophila melanogaster and at the same time inhibits classical apoptosis pathways. Proc Natl Acad Sci USA 110, E1724-33.
Horowitz B, Sharf R, Avital-Shacham M, Pechkovsky A, and Kleinberger T. 2013. Structure- and modeling-based identification of the adenovirus E4orf4 binding site in the protein phosphatase 2A B55α subunit. J Biol Chem. 288, 13718-27.
Brestovitsky A, Sharf R, Mittelman K, and Kleinberger T. 2011. The adenovirus E4orf4 protein targets PP2A to the ACF chromatin-remodeling factor and induces cell death through regulation of SNF2h-containing complexes. Nucleic Acids Res. 39, 6414-6427.
The adenovirus E4orf4 protein is rapidly recruited to DNA damage sites
The accumulation of E4orf4-GFP at a laser-microirradiated site is shown (marked with a white arrow).