Our contribution to Chronic Lymphocytic Leukemia (CLL) genome sequencing.

Our work

This laboratory belongs to the Department of Biochemistry and Molecular Biology from the Universidad de Oviedo, and to the Instituto Universitario de Oncología del Principado de Asturias (IUOPA). The main focus of Lopez-Otin lab is the identification and characterization of proteolytic enzymes involved in human pathologies, with special interest in those implicated in cancer progression. Over the last 15 years our laboratory has identified more than 60 novel human proteases from different catalytic classes, including many metalloproteinases of the MMP and ADAMTS families; serine proteases such as matriptase-2 and the polyserases; cysteine proteases including several cathepsins, multiple ubiquitin-specific proteases and the four members of the family of autophagins. Other proteases identified in our lab include FACE-1/Zmpste24 and FACE-2/Rce1, involved in the maturation of prenylated proteins such as prelamin A and oncoproteins of the Ras family.

To understand the biological function of proteolytic enzymes, we have also characterized several proteases from different model organisms, including mouse, Caenorhabditis elegans, Drosophila melanogaster or Arabidopsis thaliana. Functional studies with knockout animals have led us to clarify the biological and pathological roles of some of these novel proteolytic enzymes. Thus, recent studies have allowed us the identification of novel functions for several proteases in early stages of tumor progression. We have also provided in vivo evidence that some proteases such as collagenase-2 (MMP-8) are able to protect against cancer progression. Further studies have extended these findings to other proteases from different catalytic classes and have facilitated the building of a conceptual framework to separate the pro- and anti-tumour activities of these enzymes.

Studies with mutant mice have also allowed us to identify the in vivo substrates of some proteases, such as FACE-1/Zmpste24 which cleaves prelamin A and plays a central role in the nuclear envelope organization. Furthermore, our finding that the dramatic accelerated aging exhibited by Zmpste24-/- mice is associated with the chronic activation of the p53 tumour suppressor pathway has provided experimental support to the hypothesis of an antagonistic pleiotropy between cancer and aging. This progeroid mouse model generated at our laboratory has also allowed us to explore the possibility that stem cell alterations underlie normal aging processes. Likewise, we have recently found that the premature aging phenotype of these mice can be rescued by using genetic and pharmacological approaches aimed at lowering the levels of prelamin A accumulated in the nuclear envelope of cells from these mutant mice. These findings have opened for the first time the possibility to develop therapeutic approaches for the devastating human progeroid syndromes.

These works provide some examples of the absolute need of a tight control of proteolytic activities in human cells and tissues. An increase in protease levels may favour tissue-destructive processes like those taking place in cancer, whereas specific protease deficiencies may cause many other pathological conditions including premature aging syndromes. These ideas have been the basis of our proposal of global approaches to the analysis of proteolytic systems, through the introduction of new concepts such as Degradomics and Degradome, and novel experimental approaches to provide support to these ideas. Finally, our experience in the genomic analysis of proteases and their inhibitors has allowed us to contribute to the sequencing and annotation of diverse mammalian genomes including those of rat, platypus and chimpanzee, our closest relative. Hopefully, this multidisciplinary approach to the study of proteolytic systems will facilitate new views of this complex group of protein sculptors that decisively influence the rhythms of cell life and death in all living organisms.