Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients

Abstract

Defects in the NF1 gene have been implicated in the inherited disorder neurofibromatosis type 1, which is characterized by several developmental abnormalities including an increased frequency of benign and malignant tumours of neural crest origin (neurofibromas and neurofibrosarcomas respectively). The NF1 gene encodes a ubiquitous protein homologous to p120GAP, the GTPase-activating protein (GAP) for the products of the ras protooncogenes. When expressed in non-mammalian systems, the region of the NF1 gene homologous to p120GAP produces a protein with GAP-like activity. Here we present evidence that the ras proteins in malignant tumour cell lines from patients with type 1 neurofibromatosis are in a constitutively activated state, as judged by the guanine nucleotide bound to them, and are necessary for cellular proliferation. These cells contain p21ras and p120GAP that are both functionally wild type, but barely any functional NF1 protein. Our results show that the NF1 protein is normally essential for correct negative regulation of ras proteins in the cell, even in the presence of normal p120GAP, and they support the hypothesis that NF1 is a tumour-suppressor gene whose product acts upstream of ras.

Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation

“…In support of this mechanism, several studies have shown that neuro®bromin suppresses cell growth by inhibiting p21-ras activity in some cell types. These results are consistent with the notion that the tumor suppressor function of neurofibromin is related to its ability to operate as a GAP molecule (Basu et al, 1992;DeClue et al, 1992;Bollag et al, 1996;Largaespada et al, 1996). However, little is known about the function of neuro®bromin in astrocytes relevant to the development of astrocytomas in individuals a ected with NF1.…”

Many roads lead to oncogene-induced senescence

“…This hypothesis has been formally proven by analysing the consequences of inactivating the NF1 tumor suppressor, the gene responsible for the familial cancer syndrome neurofibromatosis type I (NF1) (Courtois-Cox et al, 2006). NF1 encodes a RasGAP protein, and its inactivation has been shown to cause an acute activation of (endogenous) Ras and Ras effector pathways (Basu et al, 1992;DeClue et al, 1992). Similar to MEFs expressing a single activated K-ras allele, inactivation of NF1 via shRNA constructs results in the immortalization of this cell type (Courtois-Cox et al, 2006).…”

The ecology of brain tumors: lessons learned from neurofibromatosis-1

“…Sequence analysis of the predicted NF1 protein sequence revealed that it contains a small domain with striking similarity to the catalytic segment of a family of proteins termed GTPase activating proteins. Neurofibromin was subsequently shown to be a Ras-GTPase activating protein, accelerating the conversion of active GTPbound Ras to inactive GDP-bound Ras (Ballester et al, 1990), such that loss of neurofibromin expression results in increased Ras activity and increased Ras-driven cell proliferation (Basu et al, 1992; DeClue et al, 1992).…”