Understanding the role of the HIPK kinase family in health and disease
Division of Cancer Research
Jaqui Wood Cancer Centre
University of Dundee
James Arrott Drive
Ninewells Hospital and Medical School
+(44) 01382 383990
Laureano de la Vega is a biochemist graduate from the University of Cordoba (Spain), he finished his PhD in Biochemistry in 2007 obtaining the highest degree, Summa Cum Laude, for his work investigating the molecular mechanisms regulating HIV latency. Following this, he moved to Giessen (Germany) to join the team of Prof. Lienhard Schmitz as a postdoctoral researcher from 2007 to 2013. During that time his research was focused on post-translational modifications of HIPK2, an important regulator of cell growth, cell death and differentiation. In 2013 he moved to Dundee where he started his own group focused on regulation of cancer-related proteins by post-translational modification and their relevance in tumour progression and chemoresistance acquisition..
Organisms need to be able to adapt to change in order to survive, and certain cellular programs (stress response pathways) have evolved to respond to a dynamic environment. Example of stress responses pathways include p53, NRF2, and NF-κB pathways. Stress responses are by definition acute, and their transient activation help normal cells to cope with cellular stresses. Interestingly, there is a large body of evidence showing that, in contrast to normal cells, cancer cells are constitutively under cellular stress (i.e. DNA damage/replication stress, proteotoxic stress, mitotic stress, metabolic stress, and oxidative stress) and they depend on the sustained activation of cytoprotective stress response pathways to survive.
The essential nature of the stress response pathways in cancer cells makes them attractive targets, and thus, a better understanding of how these pathways are regulated could help identify new ways to modulate stress responses to impair cancer cell survival. In that sense, our lab is focused in obtaining a detailed understanding of stress response pathways and their aberrations in cancer. For that, we are interested not only on key master regulators of stress responses (e.g. NRF2 or p53) but as well in the upstream regulatory pathways that modulate their activity (i.e. upstream kinases).
Homeodomain-Interacting Protein Kinases (HIPKs) are a subfamily of the Dual specificity tYrosine Regulated Kinase (DYRK) family of kinases. These kinases function as hubs for a wide variety of stress signals, ranging from DNA damage and hypoxia to reactive oxygen species and metabolic stress. HIPK/DYRKs function as integrators for these stress signals and modulate different downstream pathways in order to allow cells to cope with these situations. Different posttranslational modifications modulate the activity and physiological role of HIPK/DYRKs, and the study of how their activity is regulated in different pathophysiological scenarios is an important line of investigation in cancer research.
Based on the literature and on previous studies from the lab it has become apparent that HIPK/DYRKs can play a dual role in cancer; either inducing apoptosis or promoting cell survival. While the pathways involved in their tumour suppressor role are relatively well studied, the underlying mechanisms mediating their pro-survival function(s) are not well characterised. Specifically, we are interested in i) understanding how this family of kinases is regulated in cancer cells; ii) identifying novel HIPK/DYRK-regulated pro-survival/oncogenic pathways and iii) to identify the basis for such functional duality in cancer, as it will inform us in which type of cancer or under which conditions (i.e. initial stages of cancer versus well stablished cancers) these kinases can support cancer cell survival and tumour growth.
L Torrente , C Sanchez1, R Moreno , S Chowdhry , P Cabello , K Isono , H Koseki , T Honda , JD Hayes , AT Dinkova-Kostova and L de la Vega, Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses. Oncogene (2017), 1–9
Schmitz ML, de la Vega L. New insights into the role of histone deacetylases as coactivators of inflammatory gene expression. (2014) Antioxid. Redox Signal. doi:10.1089/ars.2013.5750.
Saul VV, de la Vega L, Milanovic M, Krüger M, Braun T, Fritz-Wolf K, Becker K, Schmitz ML. (2013) HIPK2 kinase activity depends on cis-autophosphorylation of its activation loop. J Mol Cell Biol (2013) 5 (1): 27-38.
de la Vega L, Hornung J, Kremmer E, Milanovic M, Schmitz ML. (2013) Homeodomain-interacting protein kinase 2-dependent repression of myogenic differentiation is relieved by its caspase-mediated cleavage. Nucleic Acids Res. 2013 June; 41(11): 5731–5745 (Corresponding Author).
de la Vega L, Grishina I, Moreno R, Krüger M, Braun T, Schmitz ML. (2012). A redox-regulated SUMO/acetylation switch of HIPK2 controls the survival threshold to oxidative stress. Mol Cell. 2012 May 25;46(4):472-83.
de la Vega L, Fröbius K, Moreno R, Calzado MA, Geng H, Schmitz ML. (2010). Control of nuclear HIPK2 localization and function by a SUMO interaction motif. Biochim Biophys Acta. 2011 Feb;1813(2):283-978.
de la Vega L, Calzado MA, Munoz E, Schmitz ML (2009). Autoregulatory control of the p53 response by Siah-1L-mediated HIPK2 degradation. Biol Chem. 2009 Oct;390(10):1079-83.
Calzado MA, de la Vega L, Munoz E, Schmitz ML. (2009). From top to bottom: The two faces of HIPK2 for regulation of the hypoxic response. Cell Cycle. 2009 Jun 1;8(11):1659-64.
Calzado MA, de la Vega L, Möller A, Bowtell DD, Schmitz ML. (2009). An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nat Cell Biol. 2009 Jan;11(1):85-91.
Laura Torrente Fernandez (2013-2017). “An autoregulatory loop between NRF2 and HIPK2 shapes cytoprotective responses”
- Laura Torrente Fernandez (2013-2017). “An autoregulatory loop between NRF2 and HIPK2 shapes cytoprotective responses”
- Rita Moreno (Postdoctoral Researcher)
- Angus Jackson (Lab Manager)
- Gunjit Maan (Mres Student)
- Kimberley Morrison (Mres Student)
- Clara Vázquez García (Mres Student).
- Laura Torrente (PhD Student). She obtained her PhD on 2017, and she is currently a Postdoctoral Researcher in the laboratory of Dr Gina DeNicola, Moffit Cancer Center, Tampa, Florida (USA).
- Nerea Cuesta (Mres Student). She is currently a PhD student in the Institute of Infection, Immunity and Inflammation, University of Glasgow.
- Paula Cabello (Intern). She is currently a PhD Student in INCLIVA Biomedical Research Institute, Valencia (Spain).
- Carlos J. Sánchez (Intern).
- Elisenda Raga (Technician). She is currently a Research Assistant at University of Cambridge
- Tracy Boateng (Intern).
- Kristine Soriano (Intern). She is currently a MSc Student at Glasgow Caledonian University
- Amirah M Murtala (Msc Student).