Constitutive phosphorylation of Janus kinase 2 in the GL15 glioblastoma derived human cell line.
The notion that gliomas could originate from mutated glial precursor cells highlights the possibility of modulating the proliferative and migratory behaviour of glioma cells by acting on the molecular mechanisms operative during the development of the Central Nervous System (CNS), but absent in the normal adult brain. We show that the GL15 glioblastoma derived human cell line displays a high expression of nestin which, combined with the previously demonstrated high expression of vimentin, constitutes a characteristic of astrocyte restricted precursors. We also show that, in analogy with some leukaemia cells, GL15 cells display the constitutively phosphorylated form of Janus kinase 2 (JAK2), a tyrosine kinase expressed during CNS development but undetectable in the normal adult brain. The constitutive activation of JAK2 does not result from chromosomal aberrations involving the JAK2 gene, but most probably from abnormally activated transduction systems operative in glioblastoma cells. We then investigated the effects of tyrphostin AG490, an inhibitor of JAK2 autophosphorylation, on GL15 cell growth. In the absence of exogenous growth factors and cytokines, 10 microM tyrphostin AG490 induces an S phase arrest, combined with a partial impairment of the G2 phase of the cell cycle. The abnormally activated JAK2 could then potentially represent a target for a selective pharmacological approach in glioblastoma cells in which a combination of glial precursor characteristics and genetic alterations occurs.
Sciaccaluga
Miriam
M
Department of Cellular and Environmental Biology, Section of Cellular and Molecular Biology, University of Perugia, via Pascoli, 06100 Perugia, Italy.
Gianfranceschi
Gian Luigi
GL
Rocco
Simone
S
Germano
Giovanni
G
Roti
Giovanni
G
Gorello
Paolo
P
La Starza
Roberta
R
Castigli
Emilia
E
D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D005909:Glioblastoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D064231:Nestin; D010766:Phosphorylation / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D014746:Vimentin / Q000096:biosynthesis
D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; D064231:Nestin; D020032:Tyrphostins; D014746:Vimentin; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507924:JAK2 protein, human; D053614:Janus Kinase 2