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Molecular Mechanisms of Differentiation
Potential tumour suppressor role of TSC-22 gene in human brain tumours
- Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
- Institute of Neurosurgery named after A. P. Romodanov, NAMS of Ukraine
32, Manuilskogo Str., Kyiv, Ukraine, 04050
- Max Planck Institute for Molecular Genetics
Ihnestrasse 63-73, 14195 Berlin, Germany
At present some biological mechanisms assumed to initiate and promote astrocytoma formation have been partly revealed. Several putative genes in regions strongly suggested to harbour tumour suppressors should be identified. For example, these are the regions on the chromosomal arms 1p, 10p, 13q, 19g and 22g. More comprehensive approach in the analysis of astrocytomas includes gene expression determination in order to focus not only on the structural alterations but on the regulatory differences as well. Such changes in gene expression are important determinants of normal cellular physiology and, if disturbed, directly contribute to abnormal cellular physiology, including cancer. The search of new genes, the activation or inactivation of which is associated with the progression of astrocytic tumours, is still a goal of intensive investigations. In this work, more than a hundred cDNA clones differed in hybridization signals between human normal brain and glioblastoma multiform have been found by screening of high density grids of arrayed human fetal brain and human postnatal brain cDNA libraries. The repeated differential hybridization of the clones selected by primary screening, as well as the analysis of RNA from human adult normal brain and glial tumour samples have revealed 16 nucleotide sequences, which content had changed in tumours. The decreased content in astrocytic tumours has been determined for TSC-22 mRNA corresponding to cDNA in ICRFp507J 1041 clone from the library of human fetal brain cDNAs. The Northern blot hybridization of RNA from different human brain tumours has shown very low amount of TSC-22 mRNA in a bulk of the investigated samples of glioblastoma multiform, anaptastic astrocytoma, WHO grade II astrocytoma and some other tumours. The expression of TSC-22 gene has not been detected at all in astrocytoma WHO grade 11 as well as in meningioma, brain sarcoma, sarcomatous meningioma and oligodendroglioma (one sample of each tumor kind). The Southern blot hybridization has revealed the deletions in genomic loci of TSC-22 gene in two of three anaplastic astrocytomas analyzed. A significantly decreased level of the production of TSC-22 mRNA in the human brain tumours and, as it was shown previously, in the salivary gland tumours, an antiproliferative role of TSC-22 protein, the localization of TSC-22 gene in 13q14 region close to the known tumour suppressor retinoblastoma (Rb) gene, and the deletions in this genomic locus strongly evidence TSC-22 to be a tumour suppressor.
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