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Cáncer, mecanismos moleculares de la apoptosis Ver áreasVer áreas
Apoptosis Signalling Group
Institut Municipal d'Investigació Mèdica (IMIM)

 

Grupo coordinado por Gabriel Gil Gómez

Apoptosis Signalling Group
Institut Municipal d'Investigació Mèdica (IMIM)
Dr. Aiguader, 88
08003 Barcelona

Tel: 933 160 432
Fax: 933 160 410
e mail: ggil@imim.es
Web: http://www.imim.es/programesrecerca/cancer/en_copiadeubcmgil.html

 


The deregulation of DNA damage repair and signalling to cell cycle checkpoints, known as the DNA Damage Response (DDR), is associated with a predisposition to cancer and affects the responses to DNA-damaging anticancer therapy. In our laboratory we are characterizing the role of a new member of the Cyclin family of proteins (Cyclin O) in the integration of different stress responses that affect the genomic integrity of the cell.
Cyclin O was identified as a protein necessary for Cdk2 activation and apoptosis in lymphoid cells in response to glucocorticoids and DNA damaging agents. It is required for the activation of the apical apoptotic caspases and Cyclin O knockout mice have a complex phenotype characterized by deficiencies in physiological processes (both apoptosis and non-apoptosis related) that normally require caspase activation.

We have found that Cyclin O is crucial in the decision of a cell with damaged DNA to repair it by the efficient, faster but error prone Non-Homologous End Joining (NHEJ) mechanism or alternatively, by the slower and high fidelity Homologous Recombination (HR) process. In the absence of Cyclin O HR is favoured over NHEJ and our preliminary results show that, as a consequence, the process of Class Switch Recombination (CSR) of B-cells is impaired resulting in elevated IgM titers.
The process of NHEJ is potentially mutagenic and may be the origin of chromosomal translocations. We are currently characterizing the role of Cyclin O in double strand break repair and how this newly identified function is related to both its role in the apoptotic branch of the checkpoints and the process of tumorogenesis.

Recent findings show that Cyclin O knockout mice have a severe reduction in the number of cilia in the ciliated epithelium of the body (ependyma, body’s air passages, including the lungs, trachea, and nose, in the digestive tract and in the female reproductive system). Cyclin O seems to be essential for the duplication of the centriole, a crucial step in ciliogenesis. This process is intimately linked to the DNA Damage Response and its perturbations result in chromosomal instability, a common finding in many types of cancer. We intend to further understand the connection between Cyclin O overexpression in human tumours and the perturbations in the number of centrioles/centrosomes.

Miembros del grupo

Gabriel Gil Gómez, group leader
e-mail: ggil@imim.es

Francesc Alameda
N. Alexander Balsiger
Marta Garrido Saldaña

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Líneas de Investigación

  1. Estudio del papel de la Ciclina O en la regulación de la apoptosis inducida por daño genético a través de la modulación de los mecanismos de reparación del DNA.
  2. Regulación de la replicación del centriolo por la Ciclina O y su desregulación en la tumorogénesis.

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Publicaciones

Brady*, H.J.M.; Gil-Gómez*, G.; Kirberg, J. and Berns, A.J. (1996) "Baxα perturbs T cell development and affects cell cycle entry of T cells"
EMBO J. 15, 6991-7001
*Equal contribution.

Gil-Gómez, G.; Berns, A. and Brady, H.J.M. (1998) “A link between cell cycle and cell death: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis”
EMBO J. 17, 7209-7218.

Granés, F.; Roig, M.B.; Brady, H.J.M. and Gil-Gómez, G. (2004) “Cdk2 activation acts upstream of the mitochondrion during glucocorticoid induced thymocyte apoptosis” Eur. J. Immunol. 34: 2781-2790.

Roig, M.B.*; Roset, R.*; Ortet, A.; Anfosso, A.; Cabellos, L.; Garrido, M.; Balsiger, N.A.; Alameda, F.; Brady, H.J.M. and Gil-Gómez, G. (2009) “Identification of a novel Cyclin required for the intrinsic apoptosis pathway” Cell Death Diff 16: 230-243
*Equal contribution.

Garcia-Fernandez, R.A.; Garcia-Palencia, P.; Suarez, C.; Sánchez, M.A.; Gil-Gómez, G.; Sanchez, B.; Rollan, E.; Martin-Caballero, J. and Flores, J.M. (2014) “Cooperative role between p21cip1/waf1 and p27kip1 in premature senescence in epithelial proliferative lesions in mice” Histol and Histopathol 29: 397- 406.

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Proyectos de Investigación y Contratos

Autoinmunidad, inflamación, y cáncer: el papel mediador de la Ciclina O y su posible aplicación clínica como indicador temprano de transformación tumoral ISCIII PI13/00864

 

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Tesis Doctorales

Título del trabajo: The role of Cyclin O in the DNA Damage Response
Universidad: Universitat Pompeu Fabra
Doctorando: Marc Núñez Ollé
Calificación: sobresaliente cum laude
Fecha de lectura: 04/07/2014

Título del trabajo: Expression and role of cyclin O in colorectal cancer
Universidad: Universitat Pompeu Fabra
Doctoranda: Kathi Künnemann
Calificación: Apto cum laude
Fecha de lectura: 13/09/2013

Título del trabajo: Signalling of cyclin O complexes through EIF2alpha phosphorylation
Universidad: Universitat Pompeu Fabra
Doctoranda: Laura Ortet Cortada
Calificación: Sobresaliente cum laude
Fecha de lectura: 04/06/2010

Título del trabajo: Study of the regulation and signalling of Cdk2-Cyclin O complexes during apoptosis
Universidad: Universitat Pompeu Fabra
Doctorando: Ramon Roset Huguet
Calificación: Sobresaliente cum laude
Fecha de lectura: 04/04/2008

Título del trabajo: El Activador de Cdk2 Relacionado con la Apoptosis: clonaje y estudio bioquímico de su papel
regulador de la muerte celular programada
Universidad: Universitat Pompeu Fabra
Doctorando: Maurici Brunet Roig
Calificación: Sobresaliente cum laude.

 

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Patentes

AUTORES: Gabriel Gil Gómez
TÏTULO: Use of Cyclin O in a medical setting
Nº REGISTRO: PCT/EP2009/063609
ENTIDAD TITULAR: IMIM-Hospital del Mar
PAISES:
FECHA DE PRIORIDAD: 16/10/08

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