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Title: Nitric oxide mediated transcriptional regulation
Keywords: Nitric oxide, neuroblastoma, transcription, AFX, CHOP, Bcl-2.
Issue Date: 31-Dec-2005
Citation: SRIDHARAN SHIVA RANJANI (2005-12-31). Nitric oxide mediated transcriptional regulation. ScholarBank@NUS Repository.
Abstract: Nitric oxide potently effects changes in cells, including gene expression, cell cycle arrest, apoptosis and differentiation. NO protects or kills neuronal cells depending on the concentration and duration of treatment. In this study, I aimed to understand NO-mediated regulation of gene transcription leading to cell death or survival in neuroblastomas, and examined the roles of two transcription factors, AFX (Foxo-4) and CHOP. Forkheads are a family of transcription factors with a classical a??winged helixa?? and are known to be regulators of longetivity and stress resistance. Here, I found evidence for a novel mechanism of NO affecting the AFX protein. NO-induced phosphorylation at the Ser-193 in AFX and subsequent nuclear retention was observed, which correlated with changes in the DNA binding affinity of Afx and the capacity of the protein to mediate transcriptional activation. Inducible over-expression of AFX killed cells independently of NO, indicating that AFX may play a role in regulating viability of neuroblastoma cells. CHOP, an important player of the ER stress response pathway, is believed to be a possible alternative pathway for NO-mediated apoptosis. I used Tet-inducible CHOP sense and anti-sense cell lines to further investigate the role that CHOP might play in neuroblastomas. I also contributed importantly to a screening project aimed to determine the panel of transcription factors and their targets that are activated by NO. I discovered that transcriptional up-regulation of Bcl-2 protects neuroblastoma cells from NO-induced apoptosis.
Appears in Collections:Master's Theses (Open)

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