Viral control of cellular pathways and biology of tumorigenesis

Viruses are a superb system to study cellular pathways, since they have evolved a variety of mechanisms to overcome cellular defenses. Viral proteins are able to reprogram or convert hosts’ metabolic and replication functions in order to obtain an environment more favorable for viral propagation.
We have been studying the regulation of the SUMO (Small Ubiquitin-related Modifier) pathway (Figure 1) by discovering a novel viral mechanism to interfere with it. As a model system we have been using a peculiar adenoviral protein called Gam1. We demonstrated the ability of the viral protein Gam1 to degrade the SUMO E1 enzyme by hijacking endogenous cellular components of ubiquitin E3 ligases. Protein post-translational modification by ubiquitin (Ub) and the ubiquitin-like protein SUMO regulate pathways that contribute to numerous biological processes. An ongoing research theme in our lab is to understand the cross-talk between the Ub and the SUMO pathways.

We have also shown that Histone Deacetylase 1 (HDAC1) is post-translationally modified by SUMO. Mammalian histone deacetylases (HDACs) are composed of ubiquitously expressed class I, tissue specific class II, and NAD-dependent class III. Human HDACs are targets for cancer therapy. However, although the therapeutic efforts with HDAC inhibitors in the treatment of cancer are being pursued, the role of individual HDACs in tumorigenesis remains to be elucidated (Figure 2).

Work published in our laboratory demonstrated that the absence of HDAC1 and HDAC2 affects cell growth; in particular, depletion of HDAC1 results in perturbation of the cell cycle with loss of mitotic cells and increase in apoptosis. HDAC1 can also be phosphorylated, ubiquitinated and acetylated. Therefore, this project is based upon our findings that different interdependent modifications might modulate the biological function of HDAC1.


Our laboratory is therefore pursuing two major projects:

A.
The biology of HDAC1 (and HDAC2) and how its post-translational modifications cross-talk and control its activity, also in light of its potential significance as a target for cancer therapy.

B.
The regulation of the SUMO pathway, its cross-talk to the ubiquitin pathway using the viral protein Gam1 as a model system. We are also assessing whether other oncogenic viruses exploit the SUMO pathway.

1)Citro S, Chiocca S.
Listeria monocytogenes: a bacterial pathogen to hit on the SUMO pathway.
Cell Res. 2010 Jun 8.
Zupkovitz G, Grausenburger R, Brunmeir R, Senese S, Tischler J, Jurkin J, Rembold 2)M, Meunier D, Egger G, Lagger S, Chiocca S, Propst F, Weitzer G, Seiser C.
The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation.
Mol Cell Biol. 2010 Mar;30(5):1171-81.
3)Fritah S, Col E, Boyault C, Govin J, Sadoul K, Chiocca S, Christians E, Khochbin S, Jolly C, Vourc'h C.
Heat-shock factor 1 controls genome-wide acetylation in heat-shocked cells.
Mol Biol Cell. 2009 Dec;20(23):4976-84.
4)Pozzebon M, Segré CV, Chiocca S.
Inhibition of the SUMO pathway by Gam1.
Methods Mol Biol. 2009;497:285-301.
Riising EM, Boggio R, Chiocca S, Helin K, Pasini D.
The polycomb repressive complex 2 is a potential target of SUMO modifications.
PLoS ONE. 2008 Jul 16;3(7):e2704.
5)Natoli G, Chiocca S.
Nuclear ubiquitin ligases, NF-kappaB degradation, and the control of inflammation.
Sci Signal. 2008 Jan 8;1(1):pe1
6)Chiocca S.
Viral control of the SUMO pathway: Gam1, a model system.
Biochem Soc Trans. 2007 Dec;35(Pt 6):1419-21.
7)Senese S, Zaragoza K, Minardi S, Muradore I, Ronzoni S, Passafaro A, Bernard L, Draetta GF, Alcalay M, Seiser C, Chiocca S.
Role for histone deacetylase 1 in human tumor cell proliferation.
Mol Cell Biol. 2007 Jul;27(13):4784-95. Epub 2007 Apr 30.
8)Boggio R, Passafaro A, Chiocca S.
Targeting SUMO E1 to ubiquitin ligases: a viral strategy to counteract sumoylation.
J Biol Chem. 2007 May 25;282(21):15376-82. Epub 2007 Mar 28.
9)Zupkovitz G, Tischler J, Posch M, Sadzak I, Ramsauer K, Egger G, Grausenburger R, Schweifer N, Chiocca S, Decker T, Seiser C.
Negative and positive regulation of gene expression by mouse histone deacetylase 1.
Mol Cell Biol. 2006 Nov;26(21):7913-28. Epub 2006 Aug 28.
10)Boggio R and Chiocca S. Viruses and sumoylation: recent highlights.
Curr Opin Microbiol. 2006 Aug;9(4):430-6. Epub 2006 Jul 3.
11)Tago K, Chiocca S, Sherr CJ.
Sumoylation induced by the Arf tumor suppressor: a p53-independent function.
Proc Natl Acad Sci U S A. 2005 May 24;102(21):7689-94. Epub 2005 May 16.
12)Boggio R and Chiocca S.
Gam1 and the SUMO pathway.
Cell Cycle 2005 Apr;4(4):533-5. Epub 2005 Apr 15.

No projects are available to students for the current accademic year.