RESEARCH SUMMARY

Our group is interested in the relationship between virus and cancer. One of our lines of investigation is “virus as the driving force of cancer”. Viral infection has long been associated with human cancer. One of the latest links is with Kaposi´s sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi´s sarcoma, primary effusion lymphoma and multicentric Castleman´s disease.

The mechanisms by which KSHV infection may cause cancer are still being clarified. Most of the tumour cells in these neoplasms are latently infected with KSHV, suggesting that the KSHV latent genes are responsible for the viral pathogenesis. LANA2 is one of the KSHV latent proteins and has been shown to be absolutely required for the survival of the KSHV-infected primary effusion lymphoma cells.

During recent years, our group has identified some of the functions of this viral protein that suggest that LANA2 has an important role in the transforming activity of the virus. Continuing with these studies, in the last two years we have:

• Identified a new function that might contribute to the pathogenesis of the virus, the disruption of cellular PML-NBs by LANA2.
• Demonstrated that the activity of LANA2 is regulated by SUMO modification.
• Demonstrated the induction of chromosome instability by LANA2.

In addition, we are also interested in evaluating the importance of different tumour suppressors in the complex innate antiviral host defence. DNA tumour viruses have developed mechanisms to inhibit tumour suppressors. Furthermore, the activation of some tumour suppressors after interferon treatment has been described. Together, these results suggest that tumour suppressors may be important for the antiviral response of the cell, providing new links between tumour suppression and the antiviral host defence.

As a result of the studies on the regulation of virus infection by major components of the tumour suppression mechanisms of the cell carried out in the last two years, our group has:

• Identified the tumour suppressor pRb as required for the proper activation of the NF-kB pathway in response to virus infection.
  
• Discovered a new function of the deacetylase SIRT1: regulation of the proper PML-NB formation.
  

Selected Publications Marcos-Villar L, Campagna M, Lopitz-Otsoa F, Gallego P, González-Santamaría J, González D, Rodriguez MS, Rivas C. Covalent modification by SUMO is required for efficient disruption of PML oncogenic domains by Kaposi's sarcoma-associated herpesvirus latent protein LANA2. J Gen Virol. 2011 Jan;92(Pt 1):188-94. Campagna M, Herranz D, Garcia MA, Marcos-Villar L, González-Santamaría J, Gallego P, Gutierrez S, Collado M, Serrano M, Esteban M, Rivas C. SIRT1 stabilizes PML promoting its sumoylation. Cell Death Differ. 2011 Jan;18(1):72-9. Campagna M, Rivas C. Antiviral activity of resveratrol. Biochem Soc Trans. 2010 Feb;38(Pt 1):50-3. Garcia MA, Gallego P, Campagna M, González-Santamaría J, Martínez G, Marcos-Villar L, Vidal A, Esteban M, Rivas C. Activation of NF-kB pathway by virus infection requires Rb expression. PLOS One. 2009 Jul 30;4(7):e6422. Marcos-Villar L, Lopitz-Otsoa F, Gallego P, Muñoz-Fontela C, González-Santamaría J, Campagna M, Shou-Jiang G, Rodriguez MS, Rivas C. Kaposi's sarcoma-associated herpesvirus protein LANA2 disrupts PML oncogenic domains and inhibits PML-mediated transcriptional repression of the survivin gene. J Virol. 2009 Sep;83(17):8849-58.