The transcriptional regulation of maspin : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry at Massey University, Palmerston North, New Zealand
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Date
2004
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Massey University
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Abstract
Maspin (mammary serine protease inhibitor) is a tumour suppressing member of the serpin superfamily. Maspin is expressed in normal breast and prostate cells, but reportedly down regulated during progression of cancer in these tissues. Maspin has been shown to inhibit cellular migration and invasion in vitro; while in vivo, maspin has been shown to inhibit tumour growth, metastasis, and angiogenesis. Maspin also plays a role in the sensitisation of cells to induced apoptosis. These functions of maspin are independent of serine protease inhibition; however the cellular mobility function is dependent on an intact reactive site loop. Despite this knowledge, the molecular mechanisms for all reported functions of maspin are currently unknown. Maspin is reported to be transcriptionally regulated: to date Ets, Ap1, and p53 transcription factors have been shown to activate transcription of maspin by binding directly to the promoter. Androgen is reported to be a negative regulator through the binding of the androgen receptor to a hormone response element within the promoter. This hormone response element is also responsible for an increase in maspin expression in response to tamoxifen, an anti-oestrogen drug. Transcriptional regulation of maspin has also been reported to be activated by other molecules, including gamma linolenic acid, manganese containing super-oxide dismutase, and nitric oxide, the mechanisms of regulation by these molecules is unknown. Loss of maspin expression in cancerous cells lines has been attributed to loss of one or more of the activating factors, and aberrant methylation of cytosine residues resulting in chromatin compaction. This study investigated the transcriptional regulation of maspin, with the aim of identifying transcriptional effectors important to the regulation of the gene. Identification of such factors may help identify a pathway in which maspin exerts its tumour suppressor functions. To this end, the maspin promoter was cloned and functional assays carried out. identifying several putative regions of the maspin promoter which may be important for the regulation of the gene. To date, the precise activator/repressor binding sites and the cognate proteins responsible for this regulation are unidentified.
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Keywords
Maspin, Genetic transcription, Serpins, Molecular genetics, Regulation