Differential expression of Csk homologous kinase (CHK) in normal brain and brain tumors.

Abstract

Substantial evidence supports the suggestion that carboxyl-terminal Src kinase (Csk) and Csk homologous kinase (CHK), two negative regulatory kinases of the Src tyrosine kinase family, play distinct roles during development of the central nervous system (CNS). To further examine the individual roles of CHK and Csk in the CNS, the authors compared the expression patterns of Csk and CHK during differentiation of primary hippocampal neurons. Opposite patterns of expression were observed for CHK and Csk. The authors observed an increase in CHK expression and a decline in Csk expression during differentiation of primary hippocampal neurons, but no difference in Src expression levels. CHK was also expressed in astrocytes and oligodendrocytes in a differentiation-dependent manner. However, CHK expression was not detected in brain endothelial cells, transformed neuroblastoma or astrocytoma cell lines, nor in primary human neuroblastoma and glioblastoma tumors (10 cases), indicating that loss of CHK expression is associated with human brain tumors. Treatment with antisense CHK oligodeoxynucleotides blocked the neuronal process formation of primary hippocampal neurons and neuronal differentiation of PC12 cells. CHK overexpression in primary hippocampal neurons using recombinant adenovirus infection resulted both in increased CHK kinase activity and changes in neuronal morphology. In addition, CHK overexpression in neuroblastoma and astrocytoma cells inhibited their growth and proliferation. These findings strongly suggested that CHK may play a role in tumorigenesis and in the terminal differentiation of neurons within the CNS.