INCREASED NEUROFIBROMATOSIS-1 GENE-EXPRESSION IN ASTROCYTIC TUMORS - POSITIVE REGULATION BY P21-RAS

The neurofibromatosis 1 (NF1) gene has been implicated in astrocyte gr owth regulation in several studies, To determine whether loss of NF1 e xpression is associated with progression towards malignancy in sporadi c astrocytomas from individuals without NF1, twenty-eight fresh astroc ytoma operative specimens (low and high grade tumors) and seven primar y human astrocytoma cell lines were examined for NF1 mRNA and protein expression, In all astrocytomas examined, increased NF1 expression was observed in the tumors relative to normal resting astrocytes, This in creased neurofibromin expression correlated with elevated levels of ac tivated p21-ras measured in both the fresh tumor specimens and the pri mary cell lines, Furthermore, when levels of activated p21 ras were de creased in astrocytoma cells expressing the ras inhibitory Asn-17 domi nant-negative mutant, levels of neurofibromin expression decreased, In addition, fibroblasts induced to express oncogenic activated p21-ras( val12) had increased expression of NF1. These results suggested that n eurofibromin expression is increased in human astrocytic tumors as a r esult of positive feedback regulation by increased levels of activated p21-ras.