Details

Autor(en) / Beteiligte

• Arbour, Nicole

Titel

Bcl-2 family members PUMA, Noxa and Mcl -1, in p53 mediated neuronal cell death

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2007

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Involvement of Bcl-2 family proteins has been implicated in neuronal survival, injury and a number of neurodegenerative disorders. The present study was undertaken to determine the importance of Bcl-2 family members Noxa, Puma and Mcl-1 in neuronal survival and neuronal cell death following injury. Here I show that Puma, a BH3-only member of the Bcl-2 family, is required for p53-mediated neuronal cell death resulting from DNA damage injury. Further, that the transcriptional activation of p53 is required for the up-regulation of Puma and the initiation of cell death under these circumstances. I also show that Noxa, a second BH3-only member of the Bcl-2 family known to be transcriptionally up-regulated by p53, is dispensable for this form of neuronal cell death (Chapter 2). The anti-apoptotic protein Mcl-1 has been implicated on a higher level, in the regulation of the neuronal progenitor cell pool, through interactions with the Notch 1 protein. It has also shown to have a dose defendant response in that mice heterozygous for Mcl-1 display an increased sensitivity to pilocarpine induced seizure injury. The research presented here, using conditional knock out models, identifies a requirement for Mcl-1 in cortical neurogenesis. Further, I found that loss of Mcl-1 in post-mitotic neurons results in the rapid, progressive degeneration of mature cortical neurons, resulting in lethality. The mature neurons lost in these mice occur, not through an apoptotic mechanism as expected, but through an autophagic cell death pathway. This identifies McI-1 as a key player in both apoptotic and autophagic neuronal cell death. To confirm the importance of Mci-1 in neurons, and identify the mechanism of its degradation in neurons, I performed in vitro experiments showing the degradation of Mcl-1 in neurons following DNA damage induced injury, and their further protection through maintenance of Mcl-1 protein levels within the system. I also show that loss of Mcl-1 sensitizes neurons DNA damage induced injury. Further, degradation of Mcl-1 under injury conditions occurs through caspase cleavage and proteasomal degradation (Chapter 3). These studies provide insight into the mechanisms of neuronal survival, cell death and neurodegeneration. They also identify Puma and Mcl-1 as potential therapeutic targets for the treatment of neuronal injury and neurodegenerative diseases.