NUCLEAR ACCUMULATION OF FGF-2 IS ASSOCIATED WITH PROLIFERATION OF HUMAN ASTROCYTES AND GLIOMA-CELLS

FGF-2 has been implicated in the neoplastic transformation of glioma c ells and in the transition of normal quiescent astrocytes to a prolife rating, reactive state. In the present study we have observed that in human glial cells, levels and subcellular localization of FGF-2 are di fferent in quiescent and proliferating cells. FGF-2 was detected in th e cytoplasm of non-reactive astrocytes in human brain sections. In con trast FGF-2 was located within the cytoplasm and nuclei of reactive as trocytes in gliotic brain tissue and in neoplastic cells of glioma tum ors. In vitro, FGF-2 was found predominantly in the nucleus of subconf luent proliferating astrocytes, but was detected only in the cytoplasm of density arrested quiescent astrocytes. Our results suggest that re duced cell contact stimulates nuclear accumulation of FGF-2, accompany ing mitotic activation of reactive human astrocytes. FGF-2 was constit utively localized to the nucleus of continuously proliferating glioma cells independent of cell density. A role for intracellular FGF-2 was further suggested by the observation that glioma cells that are not st imulated to proliferate by extracellular FGF-2 proliferated faster whe n transfected with FGF-2 expressing vectors. This increased proliferat ion correlated with nuclear accumulation of FGF-2. Cell proliferation was attenuated by 5'-deoxy-5'-methylthioadenosine, a FGF-2 receptor ty rosine kinase inhibitor that acts within the cell, but was unaffected by myo-inositol hexakis [dihydrogen phosphate] that disrupts FGF-2 bin ding to plasma membrane receptors. Our results indicate that FGF-2 ser ves as a nuclear regulator of proliferation in astrocytic cells. In gl ioma cells, the constitutive presence of FGF-2 in the nucleus may prom ote proliferation that is insensitive to cell contact inhibition.