Hoeck, J.D. (2011) The role of Fbw7 and its substrates Notch and c-Jun in neural stem cells, the brain and development. Doctoral thesis, UCL (University College London).
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Activation of the oncogenic transcription factor c-Jun by the Jun N-terminal kinase (JNK) has been implicated in diverse biological effects, for example promoting intestinal proliferation or inducing neural apoptosis. Apart from differentiation, apoptosis plays an important role in the specification of neuronal networks in the developing brain. However, the molecular mechanisms governing differentiation and apoptosis during brain development are incompletely understood. In my PhD studies, I have shown for the first time that the E3 ubiquitin ligase substrate recognition component Fbw7 (F-box and WD repeat domain containing-7), a negative regulator of phosphorylated c-Jun and other oncoproteins such as Notch, is a key factor of differentiation and survival in the developing brain. Fbw7-deficiency caused Notchdependent accumulation of radial glia stem cells and c-Jun-dependent loss of progenitors and differentiated cells. Thus, Fbw7 acts as a key molecular switch to allow neural stem cells to differentiate and neural progenitor cells to survive by antagonising Notch and JNK/c-Jun signalling respectively. Whilst sustained JNK/c-Jun signalling contributes to abnormal brain development in conditional Fbw7-knockout mice, c-Jun activation by JNK has been suggested to be dispensable for mouse development but necessary for c-Jun oncogenic function. By mutating the four main JNK-phosphorylation sites in the Jun gene (Jun4A), I could show that Jun4A/4A mice are viable, do not exhibit histological abnormalities and are able to recover from intestinal or neural pathology. Furthermore, moderate activation of JNK/c-Jun signalling in the nervous system of ROSA26-LSL-JNKK2-JNK1ΔN/+ mice did not impair brain histology but led to slightly improved nerve regeneration. In vitro, Jun4A/4A mouse embryonic fibroblasts underwent premature senescence independent of oxidative stress and p53 levels. These findings may prove important for targeting JNK/c-Jun signalling in order to promote nerve regeneration and to inhibit tumour growth in a p53-independent manner with the potential of limited side effects.
|Title:||The role of Fbw7 and its substrates Notch and c-Jun in neural stem cells, the brain and development|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences|
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