Viral control of cellular pathways and biology of tumorigenesis
Susanna Chiocca, Ph.D.
c/o IFOM-IEO Campus
Via Adamello, 16 - 20139 Milan, Italy
Tel +39 02 57489 835 - Fax +39 0294375990
fig.1: The SUMO Pathway [+zoom]
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 hostsí 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.
fig.2: HDACs as targets for cancer therapy [+zoom]
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).
fig.3: HDAC1 and its post-translational modifications [+zoom]
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 (Figure 3).
Our laboratory is therefore pursuing two major projects:
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.
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.