Diaz del Pozo, Esther Maria; (2001) Isolation, characterisation and transcriptional control of leucocyte common antigen CD45 in the Japanese pufferfish Fugu rubripes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The leucocyte common antigen (CD45) is a high molecular weight transmembrane tyrosine phosphatase. It is expressed exclusively in nucleated haematopoietic cells. It plays a crucial role in maturation, differentiation and function of B and T lymphocytes due to the tyrosine phosphatase activity located in the intracellular region of the molecule. The intracellular and transmembrane regions of CD45 are highly conserved at the amino acid level between species, but not the extracellular region. This is highly glycosylated and is variable in size depending on the alternative splicing of exons 4, 5 and 6 (A, B and C) which gives at least five different isoforms. Although the amino acid sequence is not conserved in the extracellular region, some structures are maintained throughout evolution, such as the highly glycosylated alternatively spliced region, a cysteine rich domain and three fibronectin type three domains. The human CD45 gene is 120 kb long, located in chromosome one and composed of 33 exons. The transcriptional control of CD45 has been studied in mice and humans. No TATA box has been found. In mice, multiple transcriptional initiation sites have been demonstrated and a tissue specific promoter located in intron lb. In humans a promoter has been found in intron 1 but this did not show tissue specificity. The large size of the mammalian gene has made difficult to identify regulatory elements. The objective of this project was to study the transcriptional control mechanisms of CD45 in a simpler model. The Japanese pufferfish Fugu rubripes was chosen because it has a very compact genome, due to the reduction in non-coding DNA. However, Fugu has approximately the same number of genes as mammals and both synteny and transcriptional regulatory elements are conserved. Here we describe the isolation and characterisation of the Fugu CD45 orthologue. Both the gene and protein are highly conserved in comparison with other species. We have also identified a functional promoter in the upstream region of the gene, which does not show tissue specificity when tested in human cells. Our studies also showed the presence of a weak enhancer in intron 1. Further studies would be required to identify tissue specific elements and their homologues in humans.

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