Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Dr. Sean Cregan

Abstract

An increasing body of evidence suggests that astrocytes play a key role in modulating neuronal fate during acute and chronic neurodegenerative conditions. Following CNS injury, an upregulation of p53 has been noted in both neurons and reactive astrocytes. p53 is an extremely important protein in determining cell fate decisions and its activation can result in the transcriptional induction of target genes that regulate apoptosis, autophagy, senescence and cell-cycle arrest. We found that p53 is upregulated in primary cortical astrocytes following oxidative stress and DNA damage and that this upregulation results in the p53-dependent transcriptional induction of several target genes involved in the induction of apoptosis, autophagy and cell-cycle arrest. However, we found that oxidative stress and DNA damage induced p53 activation did not cause a significant induction of apoptosis or autophagy in astrocytes but preferentially induced cell cycle arrest. Specifically we found that p53 activation resulted in a significant induction of the cyclin-dependent kinase inhibitor p21 and a marked reduction in astrocyte proliferation as determined by XTT assay and BrdU labelling. These processes were found to be p53-dependent as they were abrogated in p53-deficient astrocytes. In summary we have determined that the primary effect of p53 activation in astrocytes in the induction of cell cycle arrest which may limit astrogliosis during CNS injury.


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