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The role of activation-induced cytidine deaminase in inflammation-induced carcinogenesis

Objective

Activation-induced cytidine deaminase (AID) is a DNA-modifying enzyme essential for somatic hypermutation and class switch recombination in B cells. However, deregulation of AID can induce mutations and chromosomal translocations in B cells thus promoting neoplastic transformation and cancer development. AID expression is controlled by several transcription factors like those of the Rel/NF-kappa B family. The NF-kappa B pathway can be activated by a variety of different stimuli and constitutive activation of NF-kappa B is implicated in various malignancies. Indeed, the well established link between chronic inflammation and cancer has been correlated to constitutive NF-kappa B activation by inflammatory cytokines. Although the expression of AID was originally thought to be restricted to B cells, it has been shown recently that stimulation with inflammatory cytokines also induces AID expression in different epithelial cells. Furthermore, expression of AID has been found in hepatocarcinomas, gastric cancer and bile duct carcinomas suggesting a link between inflammation, NF-kappaB activation, AID expression and cancer development. However, it remains unclear if in the observed cases AID expression is just a by-product of NF-kappa B activity or if AID actively contributes to cancer development and/or progression in vivo. In the proposed research project, I am aiming to address the role of AID in the development and progression of carcinomas in vivo. For this purpose, I am going to compare the tumour incidence and aggressiveness between wt and AID-/- mice in a model for colitis-induced carcinogenesis. In addition, I am planning to generate a reporter system in which the expression of the oncogenic KRasV12 mutant depends on the reversion of a STOP codon by AID. This will decrease the amount of mutations required for tumour development and will allow for the efficient tracking and quantification of AID activity in different tissues in vitro and in vivo.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

FP7-PEOPLE-IEF-2008
See other projects for this call

Funding Scheme

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Address
Calle Melchor Fernandez Almagro 3
28029 Madrid
Spain
Activity type
Research Organisations
EU contribution
€ 161 899,59
Administrative Contact
Dolores Liebanes (Ms.)