CENTRO DE BIOLOGÍA MOLECULAR SEVERO OCHOACaptura de pantalla 2022 09 14 a las 10.27.10    

Regulation and function of proinflammatory mediators and their involvement in immune and inflammatory mediated diseases

Research summary:

We analyzed the involvement of Toll-like receptors (TLR)/NFAT/Cyclooxygenase (Cox)-2/prostaglandins (PGs) in the immune system and inflammatory pathologies as Obesity, Cancer and Sepsis. PGF2α negatively regulates adipocyte differentiation through transcription factor NFAT. Moreover, NFATc4 deficiency plays a key role in obesity and fatty acid metabolism. Cox-2 inhibitors reduce cancer but have side effects.  As an alternative, we have analyzed genes  regulated  by  Cox2 that may provide a protooncogenic advantage. Among those, we identified, mPGES1 is involved in increased growth and induced through a PGF2α/Egr-1 mechanism. Moreover PGF2α induced TGFβ-PMEPA1 pathway, which is a critical mediator of epithelial plasticity and ovarian carcinoma progression. Dual-specificity phosphatase 10  (Dusp10) controls stress response to serum deprivation and confluence arrest and binds and dephosphorylates Yes-associated protein 1 (YAP) in colorectal cancer progression.

Image

Figure 1.  Dusp10 Role in Colon Cancer.  Upon cell contact (HD), normal cells undergo  growth inhibition in part due to YAP1  phosphorylation in Ser 127 and Ser397  by HIPPO/LATS  pathway leading to subsequent degradation. In colon cancer cells Dusp10 is induced, dephosphorylates Ser397 and translocate YAP1 back to the  nucleus where it activates transcription.

TCFL5, initially cloned by us as CHA, is a member of the bHLH transcription factor family. We found that human TCFL5 gene locus is a complex with 4 isoforms. Besides, we performed interactome analysis of all TCFL5 isoforms. The 2 major isoforms, TCFL5 and CHA, will result from alternative promoter usage and differential transcription, rather than from gene splicing. We have confirmed binding to those promoters of Notch1, Egr1 and c-Myc.  We found that CHA isoform, but not TCFL5 can bind to c-Myc and repressed its transcriptional activity in several cancer cell lines. Notch1 can bind to TCFL5 promoter and induce TCFL5 isoform. On the contrary, c-Myc can induce both TCFL5 and CHA transcription. We have also defined a set of genes regulated by TCFL5/CHA in leukemia cell lines and established its role in the prognosis and development of B-and T-acute lymphoblastic leukemia and in normal hematopoiesis.

The protozoan parasite, Trypanosoma cruzi causes Chagas’ disease. We addressed the impact of T. cruzi genetic variability in the clinical outcome and immunopathology of the disease. We addressed the role that T cell CD4+ subsets, myeloid subclasses including myeloid-derived suppressor cells (MDSC) have in the immunopathogenesis with special focus on myocarditis, both in animal models and in patients, which differ depending of the infecting strain. To address this enormous complexity we used a system biology multiomic approaches including genomics, transcriptomic, metabolomics, etc. We have found many metabolic, miRNA and mRNA  transcription alterations in T. cruzi infection suggesting a stressful condition in the heart. Serum miRNAS are excellent Biomarkers of Chagas’ disease progression. Besides, we defined Slamf1 as a new T. cruzi receptor.

Image

Figure 2. Expression of TCFL5 in B lymphocytes of germinal centers upon activation of differentiation. Image of a mouse lymphoid germinal center stained with TCFL5 (red) or Bcl6, a marker of the germinal center (green), upon activation with SRBC.

Image


* For external calls please dial 34 91196 followed by the extension number
Last nameNameLaboratoryExt.*e-mailProfessional category
Fresno EscuderoManuel2264565mfresno(at)cbm.csic.esEmérito
García PrietoTeresa2264572teresa.garcia(at)cbm.csic.esTitulado Sup.de Actividades Técn. y Profes. GP1
Herreros CabelloAlfonso2264735Tit.Sup.Activ.Técn.y Profes. GP1
Lahera AlonsoAntonio3274653a.lahera(at)cbm.csic.esInvestigador Indef. GP1
Maroto GonzálezCarolina2264572cmaroto(at)cbm.csic.esTécnico UAM
Merino ValverdeJavier2264572javier.merino(at)cbm.csic.esTitulado Sup.de Actividades Técn. y Profes. GP1
Olivares VaquerizoNatalia2264572Estudiante
Polo NicoliSergio2264529Contrato Predoctoral
Sanz RoselloMaría Magdalena2264572/ 914978604magdalena.sanz(at)uam.esCuerpo Gral. Administrativo
Stamatakis AdrianiKonstantinos2264572kstamatakis(at)cbm.csic.esProfesor Ayudante Doctor

Relevant publications:

  • Jimenez-Segovia A, Mota A, Rojo-Sebastian A, Barrocal B, Rynne-Vidal A, Garcia-Bermejo ML, Gomez-Bris R, Hawinkels L, Sandoval P, Garcia-Escudero R, et al. Prostaglandin F2alpha-induced Prostate Transmembrane Protein, Androgen Induced 1 mediates ovarian cancer progression increasing epithelial plasticity. Neoplasia. 2019;21(11):1073-84.
  • Jimenez-Martinez M, Stamatakis K, and Fresno M. The Dual-Specificity Phosphatase 10 (DUSP10): Its Role in Cancer, Inflammation, and Immunity. Int J Mol Sci. 2019;20(7).
  • Jimenez-Martinez M, Ostale CM, van der Burg LR, Galan-Martinez J, Hardwick JCH, Lopez-Perez R, Hawinkels L, Stamatakis K, and Fresno M. DUSP10 Is a Regulator of YAP1 Activity Promoting Cell Proliferation and Colorectal Cancer Progression. Cancers (Basel). 2019;11(11).
  • Callejas-Hernandez F, Gutierrez-Nogues A, Rastrojo A, Girones N, and Fresno M. Analysis of mRNA processing at whole transcriptome level, transcriptomic profile and genome sequence refinement of Trypanosoma cruzi. Sci Rep. 2019;9(1):17376.
  • Fresno M, and Girones N. Regulatory Lymphoid and Myeloid Cells Determine the Cardiac Immunopathogenesis of Trypanosoma cruzi Infection. Front Microbiol. 2018;9(351.
  • Callejas-Hernandez F, Rastrojo A, Poveda C, Girones N, and Fresno M. Genomic assemblies of newly sequenced Trypanosoma cruzi strains reveal new genomic expansion and greater complexity. Sci Rep. 2018;8(1):14631.
  • Callejas-Hernandez F, Girones N, and Fresno M. Genome Sequence of Trypanosoma cruzi Strain Bug2148. Genome Announc. 2018;6(3).
  • Santi-Rocca J, Fernandez-Cortes F, Chillon-Marinas C, Gonzalez-Rubio ML, Martin D, Girones N, and Fresno M. A multi-parametric analysis of Trypanosoma cruzi infection: common pathophysiologic patterns beyond extreme heterogeneity of host responses. Sci Rep. 2017;7(1):8893.
  • Rodriguez-Angulo H, Marques J, Mendoza I, Villegas M, Mijares A, Girones N, and Fresno M. Differential cytokine profiling in Chagasic patients according to their arrhythmogenic-status. BMC Infect Dis. 2017;17(1):221.
  • Carbajosa S, Gea S, Chillon-Marinas C, Poveda C, Del Carmen Maza M, Fresno M, and Girones N. Altered bone marrow lymphopoiesis and interleukin-6-dependent inhibition of thymocyte differentiation contribute to thymic atrophy during Trypanosoma cruzi infection. Oncotarget. 2017;8(11):17551-61.

Doctoral theses:

  • POVEDA CUEVAS, CRISTINA. Influence of Trypanosoma cruzi and host genetic variability on Chagas disease immunopathology. Director: Manuel Fresno. Abril, 2017. Apto Cum Laude. 2017. Departamento de Biología Molecular. Universidad Autónoma de Madrid.
  • JIMENEZ MARTÍNEZ, MARTA. La fosfatasa DUSP10 es un gen inducido por la ciclooxigenasa 2, implicado a través de la regulación de YAP1 en el desarrollo del cáncer colorrectal. Directores: Manuel Fresno y Konstantino Stamatakis. Julio 2017. Apto Cum Laude. 2017. Departamento de Biología Molecular. Universidad Autónoma de Madrid.
  • JIMÉNEZ SEGOVIA, ALBA. Identification of PMEPA1 as a cyclooxigenase-2 induced gene and its potential implication in cancer progression. Junio, 2017. Manuel Fresno y Konstantino Stamatakis. Junio 2017. Apto Cum Laude. 2017. Departamento de Biología Molecular. Universidad Autónoma de Madrid.

Patents:

  • Uso de una composición farmacéutica para la fabricación de un medicamento para el tratamiento y/o prevención del daño renal agudo.
    • Número: 2015/8438 (de solicitud) y 201531328 (nº de patente)
    • Propietarios: U. Autónoma de Madrid y Fundación Jiménez Díaz
    • Inventores: Manuel Fresno Escudero; Alberto Ortiz Arduán; María Dolores Sánchez-Niño
    • Fecha de solicitud: 21/05/2018 (concesión)

Projects:

  • Fresno  Escudero,  Manuel.  HOMIN:  Host-microbe  interactions  in  health  and  disease. Interface with the immune system. 317057. Marie Curie Action (ITN). Comisión Europea.2013-2017.
  • Fresno Escudero, Manuel. Red de Investigación Colaborativa en Enfermedades Tropicales (RICET). RD16/0027/0006. ISCIII. 2017-2021.
  • Manuel Fresno (Coordinador). B2017/BMD-3671. INFLAMUNE-CM. NUEVOS MECANISMOS MOLECULARES Y CELULARES IMPLICADOS EN LA FISIOPATOLOGÍA INMUNE Y ENFERMEDADES INFLAMATORIAS. Organismo financiador: Comunidad de Madrid. 2018-2021. 
 

NOTE! This site uses cookies and similar technologies.

If you not change browser settings, you agree to it. Learn more

I understand

COOKIES POLICY

What are cookies?

A cookie is a file that is downloaded to your computer when you access certain web pages. Cookies allow a web page, among other things, to store and retrieve information about the browsing habits of a user or their equipment and, depending on the information they contain and the way they use their equipment, they can be used to recognize the user.

Types of cookies

Classification of cookies is made according to a series of categories. However, it is necessary to take into account that the same cookie can be included in more than one category.

  1. Cookies according to the entity that manages them

    Depending on the entity that manages the computer or domain from which the cookies are sent and treat the data obtained, we can distinguish:

    • Own cookies: those that are sent to the user's terminal equipment from a computer or domain managed by the editor itself and from which the service requested by the user is provided.
    • Third party cookies: those that are sent to the user's terminal equipment from a computer or domain that is not managed by the publisher, but by another entity that processes the data obtained through the cookies. When cookies are installed from a computer or domain managed by the publisher itself, but the information collected through them is managed by a third party, they cannot be considered as own cookies.

  2. Cookies according to the period of time they remain activated

    Depending on the length of time that they remain activated in the terminal equipment, we can distinguish:

    • Session cookies: type of cookies designed to collect and store data while the user accesses a web page. They are usually used to store information that only is kept to provide the service requested by the user on a single occasion (e.g. a list of products purchased).
    • Persistent cookies: type of cookies in which the data is still stored in the terminal and can be accessed and processed during a period defined by the person responsible for the cookie, which can range from a few minutes to several years.

  3. Cookies according to their purpose

    Depending on the purpose for which the data obtained through cookies are processed, we can distinguish between:

    • Technical cookies: those that allow the user to navigate through a web page, platform or application and the use of different options or services that exist in it, such as controlling traffic and data communication, identifying the session, access to restricted access parts, remember the elements that make up an order, perform the purchase process of an order, make a registration or participation in an event, use security elements during navigation, store content for the broadcast videos or sound or share content through social networks.
    • Personalization cookies: those that allow the user to access the service with some predefined general characteristics based on a series of criteria in the user's terminal, such as the language, the type of browser through which the user accesses the service, the regional configuration from where you access the service, etc.
    • Analytical cookies: those that allow the person responsible for them to monitor and analyse the behaviour of the users of the websites to which they are linked. The information collected through this type of cookies is used in the measurement of the activity of the websites, applications or platforms, and for the elaboration of navigation profiles of the users of said sites, applications and platforms, in order to introduce improvements in the analysis of the data of use made by the users of the service.

Cookies used on our website

The CBMSO website uses Google Analytics. Google Analytics is a simple and easy to use tool that helps website owners to measure how users interact with the content of the site. You can consult more information about the cookies used by Google Analitycs in this link.

Acceptance of the Cookies Policy

The CBMSO assumes that you accept the use of cookies if you continue browsing, considering that it is a conscious and positive action from which the user's consent is inferred. In this regard, you are previously informed that such behaviour will be interpreted that you accept the installation and use of cookies.

Knowing this information, it is possible to carry out the following actions:

  • Accept cookies: if the user presses the acceptance button, this warning will not be displayed again when accessing any page of the portal.
  • Review the cookies policy: the user can access to this page in which the use of cookies is detailed, as well as links to modify the browser settings.

How to modify the configuration of cookies

Using your browser you can restrict, block or delete cookies from any web page. In each browser the process is different, here we show you links on this particular of the most used browsers:

fondosocialeuropeo-300px.png
Ministerio-de-Ciencia-e-Innovacin-600px.png
Comunidad-de-Madrid-600Bpx.png
agenda20-30-600px.png
fundacion-areces600px0710.png
LOGO_ERC.jpg
hrexcellence.jpg
worldwidecancerresearch-600px0710.png
aecc-600tpx.png
bbva-fund-400.png
Niemann-Pick-400px.png
wilderfund-400px.png
AliciaKoplowitz-400px.png
la-caixa-fund-600px.png
inocente-inocente-600px.png
cure-alzheimers-fund-600px.png
citrin-foundation.png
tatiana-fund02-600bpx1.png
campus-excelencia-600x400px.png
fundacion-uno-entre-cien-mil-v02.png