Transcriptional regulation and role of B-FABP and GFAP in malignant glioma

The failure of traditional therapy for patients with malignant glioma has prompted many studies to examine the mechanisms of glial cell differentiation in the hope that it will lead to the development of novel therapies designed to induce malignant glioma tumour cells to undergo differentiation. In the mammalian central nervous system, brain-fatty acid binding protein (B-FABP) and glial fibrillary acidic protein (GFAP) are both expressed in the glial cell lineage, but at different developmental stages. B-FABP is involved in the establishment and maintenance of radial glial cell differentiation in the developing brain, while GFAP is expressed in mature astrocytes. In the experiments described in Chapter 3, three nuclear factor I (NFI)-binding sites in the GFAP promoter are identified and specific members of the NFI family, mainly NFI-A and NFI-X, are implicated in the coordinate regulation of B-FABP and GFAP. In Chapter 4, through the restoration or suppression of B-FABP and/or GFAP expression in malignant glioma cell lines, we show that the expression of these proteins in malignant glioma is associated with a less aggressive phenotype. Moreover, we report that the localization of B-FABP to the nucleus correlates with its ability to mediate these phenotypic characteristics. Together, our results indicate that in malignant glioma B-FABP and GFAP expression is coordinately regulated by NFI proteins and that the expression of these proteins leads to a more differentiated state.