Increased neurofibromatosis 1 gene expression in astrocytic tumors: Positive regulation by p21-ras

The neurofibromatosis 1 (NF1) gene has been implicated in astrocyte growth regulation in several studies. To determine whether loss of NF1 expression is associated with progression towards malignancy in sporadic astrocytomas from individuals without NF1, twenty-eight fresh astrocytoma operative specimens (low and high grade tumors) and seven primary 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 increased neurofibromin expression correlated with elevated levels of activated p21-ras measured in both the fresh tumor specimens and the primary cell lines. Furthermore, when levels of activated p21 ras were decreased in astrocytoma cells expressing the ras inhibitory Asn-17 dominant-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 neurofibromin expression is increased in human astrocytic tumors as a result of positive feedback regulation by increased levels of activated p21-ras.