Research Programmes
Molecular Medicine
Cell signalling
Carme Caelles
Group Leader
Professor (Biochemistry and Molecular Biology Dept.- UB)
Office Tel : +34 93 403 71 30
Lab Tel : +34 93 403 71 31
e-mail : carme.caelles
irbbarcelona.org
Background
Cells are subjected to a myriad of signals, from the extracellular environment or generated endogenously. These signals trigger a variety of pathways, in which regulatory and cross-talk mechanisms operate to orchestrate an appropriate cellular response.
The interaction between the glucocorticoid receptor (GR), a member of the nuclear hormone receptor (NR) superfamily, and the Jun N-terminal kinase (JNK)/AP-1 signalling pathway is paradigm of cross-talk between two major signal transduction pathways. In addition, this cross-talk may underlie the pharmacological actions of glucocorticoids and also the resistance to glucocorticoid treatment frequently observed in vivo.
Protein phosphorylation cascades are a common feature in signalling pathways, including those involved in the regulation of the processes that lead to the division and multiplication of eukaryotic cells. For example, several protein kinase families, such as Aurora, Polo and NIMA/Nek kinases, collaborate with CDK1 in the initiation and execution of cell mitosis. Of these, the least studied are the NIMA kinases, or Neks, a family that is emerging as a central regulator of microtubule machinery, including the mitotic spindle.
Research Interests
Our group studies the regulatory and cross-talk mechanisms that underlie signal transduction.
We examine the mechanisms that underlie the inhibition of JNK by these NRs as well as the physiological and/or pharmacological actions (such as anti-inflammatory and anti-diabetic actions, respectively) derived from this ligand-mediated inhibitory activity. We also address the function and regulation of Nercc1 Nek6/7 in relation to other mitotic signalling cascades, and examine whether are associated with some of the mitotic aberrations observed in cancer cells.
Research Lines
Regarding the study of the cross-talk between GR or PPAR-γ, and the JNK/AP-1 pathway, we examine the molecular mechanisms underlying these interactions. These two cross-talk mechanisms are negative and occur in both directions, that is, activation of either one of these NRs down-regulates the JNK/AP-1 signalling pathway and vice versa. Using genetically modified mice, we study the antagonism of JNK/AP-1 by these NRs, as a mediator of the pharmacological actions of their ligands. In this regard, glucocorticoids display anti-inflammatory, anti-proliferative and immunosuppressive properties, and thiazolidinediones, which are synthetic ligands of PPAR-γ, are insulin sensitizer agents in clinical use for the treatment of type 2 diabetes. In the context of the mutual interference between these pathways, we analyze the involvement of the exacerbated activity of the JNK/AP-1 signal transduction pathway, observed in some disorders such as rheumatoid arthritis or asthma, in the decreased therapeutic response to glucocorticoids. On the basis of this study, we are currently designing and assaying add-on therapies to remediate this lack of response and/or to potentiate their pharmacological profile.
Our studies of mitotic pathways comprising the NIMA/Nek family of mitotic protein kinases seek to identify the cellular signals that regulate the activity of the Nercc1/Nek6/7 cassette though the cell cycle, and therefore to determine how Nercc1 activity is controlled at the molecular level and how this control is related to other mitotic signalling events. We also aim to determine the substrates and physiological functions of these kinases in relationship to the centrosome and mitotic microtubule machinery. In addition, we study whether Nercc1, Nek6 and Nek7 collaborate in the distinct molecular processes (such as the onset of aneuploidy) that lead to transformation and cancer. We also address whether the specific inhibition of these protein kinases could be used therapeutically as an anti-mitotic strategy.
Funding
This group receives financial support from the following sources:
- Fundació La Marató de TV3 ("La Marató de TV3" Foundation)
- Plan Nacional I+D+I, Ministerio de Educación y Ciencia (Ministry of Science and Education)
- Marie Curie International Reintegration Grant. European Commission
- Generalitat de Catalunya (Government of Catalonia)
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