Research interests
Function and regulation of SAPK signaling pathways in eukaryotic cells.
Signal transduction pathways are the cellular information routes by which cells monitor their surrounding as well as their own state and adjust to environmental changes. Exposure of the cells to stress induces a rapid activation of the highly conserved family of MAPKs, known as SAPKs (stress-activated protein kinases).
MAPK pathways are conserved throughout eukaryotes. They consist of three tiers of protein kinases that sequentially activate each other: a MAPKKK, a MAPKK and a MAPK. This conserved module is controlled by systems consisting of sensors/receptors, G-proteins and protein kinases, which can be of different type. Protein phosphatases are negative regulators of MAPK pathways. MAPK pathways are also controlled by both feed-forward and feed-back loops. The present understanding of cellular signal transduction is restricted, at the best, to the wiring schemes of signaling pathways. Little is known about the details of their dynamic operation and the importance of quantitative, spatial and time-dependent parameters for signaling output. One of our main focuses is the study of the signaling properties of the p38/Hog1 SAPK pathway in response to cellular stress.
On the other hand, we are involved in study cell communication systems that form building blocks for biological computation devices taking advantage of our signaling studies.
Identification and characterization of proteins under the control of the yeast Hog1 MAPK.
Exposure of yeast cells to increases in extracellular osmolarity activates the stress-responsive Hog1 MAPK. Activation of the Hog1 MAPK results in induction of a set of osmoadaptive responses, which allow cells to survive in high osmolarity environments. To understand the complexity of adaptive responses driven by MAP kinases, we are trying to define the substrates regulated by Hog1 and dissect the cellular processes involved in stress adaptation.
In our laboratory, we are using a combination of genetic screens and biochemical approaches to identify novel elements of the HOG pathway, as well as new regulatory elements.
Chromatin dynamics of transcriptional stress response in yeast.
Activation of the HOG pathway is essential for the induction of adaptive responses required for cell survival upon osmostress. Among the adaptative responses where Hog1 plays an important role, there are the processes of transcriptional regulation and cell cycle control.
Regulation of gene expression is a major adaptive response required for cell survival in response to osmostress. The HOG pathway controls gene expression through several mechanisms. The MAPK not only modifies directly stress-dependent transcriptional regulators by phosphorylation, but also associates specifically to stress responsive promoters to recruit the Rpd3 histone deacetylase complex and the preinitiation transcriptional machinery. Moreover, the role of Hog1 in the regulation of the transcription cycle is not limited to transcription initiation but rather extents to the process of transcription elongation acting as a selective elongation factor for genes induced by osmostress.
Some key questions regarding the control of gene expression by the MAPK Hog1 still remain to be elucidated. Major issues are the identification of MAPK targets that are specifically modified to regulate transcription initiation, during elongation and termination, as well as the identification of new transcriptional regulators or chromatin remodeling/modifying factors necessary for a proper transcriptional response upon osmostress. Furthermore, it is also important to characterize if the MAPK Hog1 regulates other aspects of mRNA biogenesis; for instance mRNA maturation, mRNA export or mRNA stability. Last but not least, it is of great interest to study the role of Hog1 in the control of mRNA translation in response to stress.
Cell cycle control by Hog1 MAPK in yeast.
Regulation of cell cycle is another general stress response critical for cell survival upon stress. Studies on yeast have served to understand how MAPKs control cell cycle progression in response to stress. We have found a number of molecular strategies to modulate cell cycle progression which are of great complexity: down regulations of different cyclins, stabilization of inhibitors, delocalization of key molecules, etc.
Moreover, we also showed that MAPKs are vigilant guards capable to act immediately in different phases of the cycle. A difference of internal stimuli that produces delimitated checkpoints in a determinate phase of the cycle, stress stimuli induce different checkpoints at different parts of the cycle. The Hog1 MAPK is able to induce cell cycle modulation at G1, S, G2 and exit from mitosis. Hence, we propose the existence of an osmocheckpoint: a complex response that could offer protection to cells in wherever phase of the cell cycle.
Molecular basis to stress-adaptation by p38 MAPK in mammalian cells.
The use of unicellular models have been instrumental to uncover complex responses. From yeast studies, we propose that in response to stress mammalian SAPKs could also coordinate different mechanisms to arrest cell cycle.
The HOG signal transduction pathway is highly conserved both structurally and functionally, in higher eukaryotic cells. Our laboratory is trying, to unravel whether the functions of the yeast Hog1 are also carried out by MAP kinases of the SAPK family, such as p38 and JNK, in mammalian cells.
Funding
Spanish Government:
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Genomic instability (Consolider). 2008-2013.
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Study of the role of chromatin in regulating induced transcription in response to heat stress (BFU2008-00530). 2009-2011.
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Cell cycle control by p38 MAPK in mammalian cells (BFU2007-66503). 2007-2010.
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Control de la Expresión Génica y del Ciclo Celular por Quinasas de Respuesta a Estrés (BIO2009_07762). 2010-2012
European Commission:
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UNICELLSYS (7th FP). 2008-2013.
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CELLCOMPUT (6th FP). 2007-2011.
European Science Foundation:
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Function and Regulation of SAPK Signaling Pathways in Eukaryotic Cells. EURYI. 2005-2010.
Marcelino Botín
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Private Foundation. 2008-2012.
Catalan Government:
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Cell Signaling Research Group: Grup Consolidat a Catalunya (2005GRC-00760).