Characterization of TRIB2 following PI3K inhibition

• Autor(a) principal: Baptista, Inês do Carmo Viegas
• Data de Publicação: 2015
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.1/7684
• topic: Ciências biomédicas; Cancro; Melanoma; Quimioterapia; Resistência

Cancer can be defined as an unbalance between cell proliferation and apoptosis. The PI3K/AKT signalling pathway is one of the most mutated pathways in cancer and is involved in cell growth and survival. The transcription factor FOXO3a is a critical effector of this pathway and its inactivation by AKT prevents the expression of genes involved in cell cycle arrest and apoptosis. The TRIB2 protein was found to be a repressor of FOXO3a, and over expressed in many types of cancer. Importantly, TRIB2confers resistance to PI3K inhibitors which are being tested in clinical trials. This work shows that following PI3K inhibitor treatment, there is an increase of the TRIB2 protein levels by reducing proteasomal degradation. Furthermore, the TRIB2 COP1 binding domain is critical for AKT activation and subsequent FOXO repression. Altogether, our results provide insight into the mechanism underlying TRIB2 mediated tumorigenesis and drug resistance implicating the binding and activation of AKT and suggests a role of TRIB2 in acquired resistance against PI3K inhibitors.