Oncogenic Viruses

Summary

It was demonstrated that viral infections contribute to a number of human cancers. Our group is interested in the study of the molecular mechanisms involved in virus-associated carcinogenesis, focusing our analyses on the pathways related to cell polarity disruption.

Research Lines

Analysis of cellular and viral factors that contribute to the carcinogenesis associated to virus infections

It is estimated that viral infections contribute to 15–20% of all human cancers. Though the knowledge of the molecular mechanisms involved in viral oncogenesisis highly relevant. For the case of cervical cancer, a frequent tumor worldwide and especially in Latin-America, it was demonstrated that 100 % of these tumors are associated to HPV infections.

Our group is interested in the study of the molecular mechanisms involved in the HPV-associated carcinogenesis, and we have focused our studies on the pathwasy related to cell polarity disruption. The E6 proteins derived from high-risk HPVs interact with a group of cell proteins bearing a protein interaction domain called PDZ (PSD95, Dlg, ZO-1). These PDZ proteins are key components of the cell-to-cell junctions and of the polarity complexes and participate in signal transduction mechanisms that regulate cell proliferation. From this, our main research line consists in the analysis of the process by which the interaction of E6 oncoprotein with PDZ proteins interferes with cell polarity and the signal transduction pathways and the consequences of this on cell transformation and tumor development. In particular, we study the interference of HPV with the expression of PDZ proteins of both adherent (Disc large, DLG1) and tight junctions (Partitioning defective 3, PAR3). For a better comprehension of these viral activities we develop histotypical and organotypical cultures, that in vitro mimic the squamous epithelium, target tissue for HPV, and we also apply high resolution fluorescence microscopic techniques.

Besides, we are analyzing the differential expression of these PDZ polarity proteins in several tumors, for the identification of potential biomarkers of malignant progression. These activities, in collaboration with public and private health institutions, have the aim of translating our research to possible clinical practices.

Recently, we extended our studies to the Human T-cell leukemia virus type I which is associated with T-cell leukemia in adults. We are investigating how the viral Tax oncoprotein alters the expression of proteins involved in the regulation of cell polarity and proliferation in a lymphoid model and how these functions can contribute to the oncogenesis.

Besides, it was shown that several no oncogenic viruses can also modify the expression of polarity and cell-to-cell junctions’ proteins and this should be important for virus entry, transmission and dissemination with consequences in the pathogenesis. Therefore, we proposed to apply our expertise for the analysis of pathogenic mechanisms related to polarity disruption for regional arbovirus.

Selected Publications

  • Bugnon Valdano, Marina; Cavatorta, Ana Laura; Morale, Mirian Galliote; Marziali, Federico; de Souza Lino, Vanesca; Steenbergen, Renske; Boccardo, Enrique and Gardiol Daniela (2016). Disc Large 1 expression is altered by Human Papillomavirus E7/E6 proteins in organotypic cultures of human keratinocytes. J Gen Virol. 2016 Feb;97(2):453-62
  • Federico Marziali, Ana Laura Cavatorta, Marina Bugnon Valdano, Florencia Facciuto and Daniela Gardiol. (2015). Transcriptional and translational mechanisms contribute to regulate the expression of Disc Large 1 protein during different biological processes. Biological Chemistry, 396(8):893-902.
  • FlorenciaFacciuto, Marina BugnonValdano, Federico Marziali, Paola Massimi, Lawrence Banks, Ana Laura Cavatorta and Daniela Gardiol. (2014). Human papillomavirus (HPV)-18 E6 oncoprotein interferes with the epithelial cell polarity Par3 protein. Molecular Oncology, 8:533-543.
  • Gardiol D. (2012). PDZ-containing proteins as targets in human pathologies.FEBS J. 279(19):3529.
  • Facciuto F, Cavatorta AL, Valdano MB, Marziali F, Gardiol D. (2012). Differential expression of PDZ domain-containing proteins in human diseases - challenging topics and novel issues. FEBS J.;279(19):3538-48.
  • Cavatorta, A.L., Facciuto, F., Bugnon Valdano, M., Giri, A., Banks, L. Gardiol, D. (2011). Regulation of Translational Efficiency by Different Splice Variants of the DLG1 5’-UTR. FEBS Journal. 278 (14), 2596-608.
  • Tomaic, V., Gardiol, D., Massimi, P., Ozbum. M., Myer, M, Banks, L. (2009). Human and primate tumour viruses use PDZ binding as an evolutionarily conserved mechanism of targeting cell polarity regulators. Oncogen. 28(1), 1-8.
  • Gammoh, N., Gardiol, D., Massimi, P. Banks, L. (2009). The Mdm2 Ubiquitin Ligase Enhances HPV E2 Transcriptional Activation. Journal of Virol. 82 (3), 1538-43.
  • Cavatorta, A.L., Giri, A.A., Banks, L. Gardiol, D. (2008). Cloning and functional analysis of the promoter region of the human Disc large gene. Gene. 424, 87-95.
  • Gardiol, D,, Zacchi, A., Petrera, F., Stanta, G., Banks, L. (2006). Human discs large and Scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progresión. International Journal of Cancer. 119(6), 1285-90.
  • Cavatorta, A.L., Fumero, G., Chouhy, D., Aguirre, R., Nocito, A.L., Giri, A.A., Banks, L. Gardiol, D. (2004). Differential expression of the human homologue of Drosophila Discs large oncosuppressor in histological samples from HPV-associated lesions as a marker for progression to malignancy. International Journal of Cancer. 111; 373-380.
  • Massimi, P., Gardiol, D., Roberts, S. Banks, L. (2003). Redistribution of the discs large tumor suppressor protein during mitosis. Experimental Cell Research. 290, 265-74.
  • Gardiol, D., Galizzi, S. Banks, L. (2002). Mutational analysis of the Discs Large tumour suppressor identifies domains responsible for HPV-18 E6 mediated degradation. Journal of General Virology. 83, 283-289.
  • Pim, D., Thomas, M., Javier, R., Gardiol, D. Banks, L. (2000). HPV E6 targetd degradation of the discs large protein: evidence for the involvement of a novel ubiquitin ligase. Oncogene. 19, 719-725.
  • Kühne, C., Gardiol, D., Guarnaccia, C., Amenitsch, H Banks, L. (2000). Differential regulation of Human papillomavirus E6 by protein kinase A. Conditional degradation of human discs large protein by oncogenic E6. Oncogen. 19 (51), 5884-5891.
  • Gardiol D, Kühne C, Glaussinger B, Lee S, Javier R, Banks L. (1999). Oncogenic human papillomavirus E6 proteins target the discs large tumour suppressor for proteasome-mediated degradation. Oncogene. 18, 5487-5496.

Collaborators

  • Dr. Lawrence Banks. Tumour Virology Lab. International Centre Genetic Engineering and Bitoechnology (ICGEB), Trieste, Italia.
  • Dr. Enrique Boccado. Laboratorio de Oncovirología. Departamento de Microbiología. Universidad de San Pablo. Brasil.
  • Hospital Provincial del Centenario, Servicios de Ginecología y de Anatomía patológica.
  • Hospital Iturraspe, Ciudad de Santa Fe. Servicio de Ginecología; Servicio de Anatomía Patológica; Unidad Funcional de Mama Nodo Santa Fe.
  • Dra. Ana Lía Nocito. Cátedra de Anatomía y Fisiología Patológicas. Facultad de Ciencias Médicas. UNR.

Grants

  • Provincia de Santa Fe.
  • FAPESP/CONICET
  • Instituto Nacional del Cáncer, Ministerio de Salud de la Nación.
  • Universidad Nacional de Rosario.

Director

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Gardiol, Daniela
Core Faculty
Email: gardiol@ibr-conicet.gov.ar
Phone: +54 341 4350596/4350661
Office Extension: 116
Laboratory Extension: 134

Researchers

  • Ana Laura Cavatorta

Postdoctoral fellows

  • Federico Marziali

Doctoral fellows

  • Dizanzo Paula

Undergraduate Students

  • Clarisse Brunet Avalos
  • Lucía Moriena

Imágenes

Expresión diferencial de la proteína de polaridad celular Disc Large (DLG1) durante el desarrollo de cáncer cervical. DLG1 es un blanco de la proteína E6 de HPV involucrado en el control de la polaridad celular. Durante el proceso de transformación maligna, asociado a infecciones por HPV, se observa una marcada disminución en los niveles de DLG1 que normalmente se distribuye en los bordes celulares (flecha).

La proteína E6 de HPV de alto riesgo interfiere con componentes de las uniones intercelulares importantes en la regulación de la polaridad celular. Par3 es un componente del complejo de polaridad Par; su distribución apical en las uniones intercelulares (z- stack, control) se mantiene en líneas que expresan E6.11 (E6 de HPV-11 de bajo riesgo oncogénico), mientras que se observa una importante deslocalización de Par3 en presencia de E6.18 (E6 de HPV-18 de alto riesgo oncogénico).