GROWTH-FACTOR REGULATION OF CELL-GROWTH AND PROLIFERATION IN THE NERVOUS-SYSTEM - A NEW INTRACRINE NUCLEAR MECHANISM

This article discusses a novel intracrine mechanism of growth-factor a ction in the nervous system whereby fibroblast growth factor-2 (FGF-2) and its receptor accumulate in the cell nucleus and act as mediators in the control of cell growth and proliferation. In human and rat brai n the levels and subcellular localization of FGF-2 differ between quie scent and reactive astrocytes. Quiescent cells express a low level of FGF-2, which is located predominantly within the cytoplasm. In reactiv e astrocytes, the expression of FGF-2 increases and the proteins are f ound in both the cytoplasm and nucleus. In glioma tumors, FGF-2 is ove rexpressed in the nuclei of neoplastic cells. Similar changes in FGF-2 expression and localization are found in vitro. The nuclear accumulat ion of FGF-2 reflects a transient activation of the FGF-2 gene by pote ntially novel transactivating factors interacting with an upstream reg ulatory promoter region. In parallel with FGF-2, the nuclei of astrocy tes contain the high-affinity FGF-2 receptor, FGFR1. Nuclear FGFR1 is full length, retains kinase activity, and is localized within the nucl ear interior in association with the nuclear matrix. Transfection of e ither FGF-2 or FGFR1 into cells that do not normally express these pro teins results in their nuclear accumulation and concomitant increases in cell proliferation. A similar regulation of nuclear FGF-2 and FGFR1 is observed in neural crest-derived adrenal medullary cells and of FG F-2 in the nuclei of cerebellar neurons. Thus, the regulation of the n uclear content of FGF-2 and FGFR1 could serve as a novel mechanism con trolling growth and proliferation of glial and neuronal cells.