Donnelly, Shaun Robert; (1998) Mechanisms of annexin gene-regulation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Members of the annexin protein family are characterised by their ability to bind to phosphohpids in a calcium-dependent manner. Since their discovery in the late 70s, a number of different family members have been found in mammals, plants and lower eukaryotes, although to date, no function has been unequivocally determined for any member. The restricted tissue-distribution of the annexins suggest that regulation occurs at the gene level. Most controversially, annexin I has been proposed to be steroid-inducible. Both annexins I and VI were found to be unresponsive to steroids at the protein and mRNA level in a range of cell-types. Also, steroids were shown to have no effect on annexin I secretion. Reporter gene analysis confirmed that the promoters for both the annexins I and VI genes are not steroid-inducible. Tmncation mutations were used to characterise the promoter regulatory elements showing that the annexin I promoter requires a functional CAAT and TATA box for activity. In contrast, these elements are not required in the annexin VI promoter. However, it is postulated that this promoter contains an "initiator element". Further, it is shown that both enhancers and repressors operate within the annexin VI promoter, and that a site for the transcription factor SPl is likely to be functional in-vivo. A region within the annexin VI promoter was shown to be homologous to non-coding regions of a number of genes, including interleukin-4. This region was found to be a cell-specific enhancer/repressor of gene activity. In response to activation of the interleukin-4 gene, a cell-specific protein complex was seen to bind to a site within the homologous region. It was shown that this protein is not a member of the STAT, NF-κT or NFκB transcription factor families. Removal of this protein-binding site profoundly influences the enhancer/repressor activity of the homologous region. Lastly, activation of the interleukin-4 gene triggers a marked reduction in the level of annexin VI protein/mRNA specifically in Jurkat cells. This suggests that interleukin-4 and annexin VI expression may be co-ordinately regulated by the action of enhancer/repressor elements within non-coding regions.

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