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Dr. Xose S. Puente
Dpto. Bioquimica y Biologia Molecular-IUOPA
Universidad de Oviedo
C/Fernando Bongera s/n 33006 Oviedo (Spain)
Email: xspuente@uniovi.es
Tel: +34 985 102 706
Fax: +34 985 103 564
Homepage: http://www.uniovi.es/degradome

The main focus of this lab is the identification and characterization of proteolytic enzymes involved in human pathologies, with special relevance in those implicated in cancer growth and progression. During the last 12 years this laboratory has identified more than 60 human proteases from different catalytic classes, including MMPs, ADAMTSs, cysteine proteases from the cathepsin family, the ubiquitin-specific proteases and the recently identified family of autophagins, implicated in death by autophagy. Other proteases include FACE-1 and FACE-2, involved in the maturation of prenylated proteins and implicated in premature ageing, as well as several serine proteases expressed by human carcinomas.

In order to understand the biological function of proteases, we have generated knockout animals for several of these genes, what has allowed us to identify lamin A as the main substrate of FACE-1, a metalloprotease whose mutation in human patients or KO animals leads to a premature ageing phenotype. Our work with animal models has also allowed us to identify proteases as key regulatory components during the initial steps of carcinogenesis. In this sense, specific deletion of the neutrophil collagenase (MMP8) gene in mouse results in increased susceptibility to skin tumors, suggesting a protective role for MMPs in cancer development. Finally, the recent availability of different mammalian genomes has allowed us to explore the complexity of the human degradome, the complete set of proteolytic genes in the human genome. We have determined that the human degradome is composed of 561 proteases, while mouse and rat degradomes are more complex, containing 641 and 626 genes respectively, underscoring the importance of proteolysis in human biology.
Christopher M. Overall, University of British Columbia, Vancouver (Canada)

Agnes Nöel, University of Liege, Liege (Belgium)
F-Xavier Gomis-Ruth, Institut de Biologia Molecular de Barcelona, Barcelona (Spain)

Gillian Murphy, University of Cambridge, Cambridge (UK)

Wolfram Bode, Max-Planck-Institute for Biochemistry, Martinsried (Germany)

Steven D. Shapiro, Harvard Medical School, Boston (USA)

Karl Tryggvason, Karolinska Institutet, Stockholm (Sweden)
Pendás, A.M., Zhou, Z, Cadiñanos, J., Freije, J.M., Wang, J., Hultenby, K., Astudillo, A., Wernerson, A., Rodríguez, F., Tryggvason, K., and López-Otín, C. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice.
Nature Genet 31, 94-9 (2002)

López-Otín, C. and Overall, C.M. Protease degradomics: a new challenge for proteomics. Nature Rev Mol Cell Biol 3, 509-19 (2002)

Overall, C.M. and López-Otín, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nature Rev Cancer 2, 657-72 (2002)

Puente, X.S., Sánchez, L.M., Overall, C. and López-Otín, C. Human and mouse proteases: a comparative genomic approach. Nature Rev Genet 4, 544-558 (2003)

Balbín, M., Fueyo, A., Tester, A.M., Pendás, A.M., Pitiot, A.S., Astudillo, A., Overall, C.M., Shapiro, S.D. and López-Otín, C. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nature Genet 35, 252-257 (2003)

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