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Regulation of gene expression and survival in cellular stress.

Janjua, S.; (2005) Regulation of gene expression and survival in cellular stress. Doctoral thesis , University of London. Green open access

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Abstract

All organisms have developed regulated mechanisms to maintain homeostasis. At the cellular level, this normal functioning of cells is regulated by expression of regulatory genes that are required for normal cell function. Most cells in multicellular organisms are capable of altering gene expression in response to extracellular signals such as elevated temperature, ischaemia/reperfusion, inflammation, infection, cytokines, and amino acid analogues. In this thesis the effects of cellular stresses in the form of elevated temperature or simulated ischaemia have been investigated. Previous studies show that elevated temperature or simulated ischaemia can induce expression of heat shock proteins (Hsps) in order to prevent misfolding of cellular proteins. Moreover, it has been shown that the stress responsive transcription factor heat shock factor-1 (HSF-1) is phosphorylated and translocates to the nucleus to bind to heat shock elements within hsp gene promoters. In addition, HSF-1 can interact with other transcription factors such as the signal transducer and activator of transcription-1 (STAT-1), which is a latent cytoplasmic transcription factor activated in response to regulatory cytokines such as interferon gamma (IFNgamma). Preliminary data shows that elevated temperature can induce expression of Hsp90 in the STAT-1 deficient cell line (U3A) treated with IFNa (activates STAT-1 and STAT-2), but reduces the levels of Hsp90 expression in the U3A cell line treated with IFNa and IFNgammain combination. These findings suggest that there may be competition between STAT-1 homodimers and STAT-1/STAT-2 heterodimers and will require further investigation The STAT-1 transcription factor has previously been demonstrated to play a role in stress-induced apoptosis. In this study, STAT-1 is shown to be required for stress-induced apoptosis using the STAT-1 deficient U3A cell line. Cells lacking STAT-1 show reduced cell death/apoptosis in response to elevated temperature or simulated ischaemia. However, expression of STAT-1 in these cells restores sensitivity to stress-induced death. The C-terminal domain alone of STAT-1 is also able to enhance stress-induced cell death, and may be acting via a novel co-activator-type mechanism. Many protective agents have been identified that are able to reduce cell death due to ischaemic injury. Cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, has been shown to protect rat neonatal cardiomyocytes subjected to simulated ischaemia via the p42/p44 MAPkinase and PI-3 Kinase pathways. In addition, the unrelated peptide urocortin (Ucn) also protects cardiomyocytes via the same pathway as CT-1 in response to simulated ischaemia and both CT-1 and Ucn induce Hsp expression. In this study, Ucn has been shown to be able to induce enhanced expression of CT-1 at mRNA and protein levels in response to simulated ischaemia. Moreover, the effect is mediated by activation of the CT-1 promoter and requires the transcription factor C/EBPp /NFIL-6. This finding indicates that a common pathway exists for these two protective agents with Ucn inducing CT-1 synthesis. Overall, the work performed indicates that multiple interacting pathways modulate the cellular stress response with either protective or damaging effects.

Type: Thesis (Doctoral)
Title: Regulation of gene expression and survival in cellular stress.
Identifier: PQ ETD:592065
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification:
URI: https://discovery.ucl.ac.uk/id/eprint/1444756
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