Gargiulo, Anna (2014) The role of Fe65 in the response to DNA damage. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: The role of Fe65 in the response to DNA damage
Date: 31 March 2014
Number of Pages: 68
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Genetica e medicina molecolare
Ciclo di dottorato: 26
Coordinatore del Corso di dottorato:
Date: 31 March 2014
Number of Pages: 68
Keywords: DDR, AKT, tumor suppressor, JNK
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Aree tematiche (7° programma Quadro): SALUTE e TUTELA DEL CONSUMATORE > Biotecnologie, strumenti e tecnologie generiche per la salute umana
Date Deposited: 10 Apr 2014 10:19
Last Modified: 15 Jul 2015 01:01

Collection description

Fe65 is an adaptor protein able to interact with many different partners. Several results supposed the possible involvement of Fe65 in the cell response to DNA damage (DDR). Indeed, Fe65 null mice are more sensitive to genotoxic stress and this increased sensitivity appears to be dependent, at least in part, on defects of DNA repair. Many results indicate that the suppression of DDR plays an important role in tumor development and progression. Mutations of various members of the DDR pathway often result in an increased tumorigenesis. To investigate the involvement of Fe65 in tumor development I analyzed the phenotype of primary embryonic fibroblasts (MEFs) derived from Fe65-/- mice. I found that the apoptosis induced by ionizing radiations, UV rays or Myc ectopic expression is lower in Fe65-/- primary MEFs. This effect is accompanied by an increase in proliferation rate with an altered cell cycle kinetics. Despite a normal phosphorylation of p53, Fe65-/- MEFs failed to accumulate BAX and PUMA mRNAs upon DNA damage. Furthermore, Fe65 -/- MEFs showed an increase of the basal levels of the phosphorylated form of AKT, which was accompanied by a slight decrease of the amount of PTEN. It was previously demonstrated that Fe65 interacts with JNK1 and γ-H2A.X. Fe65 suppression prevents the co-immunoprecipitation of these two proteins, thus suggesting that the resistance to apoptosis in Fe65-/- MEFs could be, at least in part, a consequence of the reduced activation of JNK-dependent pro-apoptotic pathway. While, as expected, early passage wild type primary MEFs are poorly sensitive to Myc-induced transformation, Myc overexpression induced the growth of a significant number of colonies of Fe65-/- cells. Similarly, the silencing of Fe65 in NIH3T3 cells significantly enhanced the transforming efficiency of oncogenic Ras. Furthermore, I found that Fe65 expression is reduced both in a transformed cell line and in human tumors and this effect doesn’t depend on gene deletion or promoter methylation. These results suggest the possibility that Fe65 is a tumor suppressor gene.


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