Mathias Schmid, M.D.
University of Ulm
Internal Medicine III
Robert-Koch Strasse 8
89081 Ulm, Germany
presenter: Mathias Schmid
Mathias Schmid, Sylvia Linortner and Hartmut Döhner
University of Ulm, Internal Medicine III, Robert-Koch Strasse 8, 89081 Ulm, Germany
Next to deletion and mutation, hypermethyltion of CpG-dinucleotides in the promoter area is another mechanism of gene inactivation. Using the SAGE database (http://www.ncbi.nlm.nih.gov/SAGE), we identified KIAA0537 as a gene with a CpG-rich promoter that is predominantly expressed in normal but not in malignant brain tissue. Multiple tissue northern blot experiments showed that KIAA0537 is also expressed in heart and lung. It belongs to the family of serine/threonine kinases and has a highly conserved catalytic domain. Phylogenetic analysis revealed a high homology to a C.elegans protein with so unknown function and to the human cdc25C phosphatase, a gene involved in cell cycle control. In four matched RNA glioma specimens (normal vs. tumor tissue from the same patient), KIAA0537 RNA was found exclusively in the normal but not in the tumor tissue. Furthermore, gene expression could be induced by the demethylating agent 5´-aza- 2´deoxycytidine in 2/5 glioma cell lines and none of the lines had a deletion at the KIAA0537 gene locus. Inhibition of histone deacetylase by Trichostatin A had no effect on KIAA0537 RNA expression. Finally, the full length KIAA0537 cDNA was cloned into a mifepristone-regulated mammalian expression vector and transfected into the human glioma cell line GMS-10. Overexpression of the KIAA0537 protein induced cell cycle arrest in G2/M phase. These data suggest that KIAA0537 might be a new tumor suppressor gene candidate that is frequently inactivated in human gliomas. In addition, our work puts emphasis on the importance of publicly accessible databases.
This work was supported by a grant from the Deutsche Krebshilfe (Schm 1083-2/1) to MS
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