Thesis

Transcriptional regulation of the Slit2 gene core promoter

The Slit2 gene, located on chromosome 4p15, codes for the production of a membrane bound and secreted glycoprotein. The Slit2 protein has been found to behave as a chemorepellent, allowing for the migration of neural crest cells and inhibiting tumor metastasis. The role of Slit2 in neural development and neoplastic growth and migration has been well characterized in a number of studies, and more recently a possible role in the mediation of the HIV virus has been proposed. However, the genetic mechanisms underlying regulation of the Slit2 gene have not been well studied. Here we identify the core promoter of Slit2 by analysis of its transcriptional activity, the trans-acting factors that contribute to this transcriptional activity, and use bioinformatics to determine the sequence homology for the Slit2 promoter region among a number of species. Data indicate that the core promoter of Slit2 lies within the -420bp promoter fragment in relation to the start site of transcription. Transcriptional analysis suggests the most important region within the Slit2 core promoter lies between -420bp and -305bp and that at least three consensus sequences for transcription factor binding sites within this region contribute to the transcriptional activity of the gene. Bioinformatics analysis of this region shows that it is highly conserved over twenty-one species, and that the DNA sequence follows an expected pattern of divergence through evolution.

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