Knowing that NF1 is degraded by the proteasome during the cell cycle, McGillicuddy et al. set out to define the signalling pathways that control NF1 degradation and determine whether these pathways might destabilize NF1 in sporadic tumours. Several lines of evidence showed that in cultured cell lines the acute proteasomal degradation of NF1 is induced by activation of protein kinase C (PKC), and that this degradation is required for Ras activation. PKC hyperactivation has been implicated in gliomagenesis, and neurofibromatosis type 1 is associated with predisposition to gliomas; therefore, the authors next examined a possible role for NF1 degradation in gliomagenesis. Both proteasome and PKC inhibitors stabilized NF1 in 8 of 15 human glioblastoma cell lines tested and in neurosphere cultures of primary human glioblastoma cells. Furthermore, expression of a fragment of NF1 that cannot be degraded suppressed xenograft tumour formation of U87 glioblastoma cells, indicating that NF1 degradation is required for tumorigenesis. Tissue from nine grade IV primary glioblastomas was obtained; the authors found that NF1 was absent or minimally expressed in four samples, and in a further four there was evidence of polyubiquitylated NF1, consistent with the cell line data.
Interestingly, the authors observed that preventing expression of NF1 using short hairpin RNA in some glioblastoma cell lines induced p53-dependent senescence. Similarly, they found that benign pilocytic astrocytomas — which often develop in patients with neurofibromatosis type 1 — express p53 and seem to undergo senescence; the authors propose that this restricts progression to glioblastoma. Sequencing of NF1 in sporadic human glioblastoma samples revealed that although null mutations in NF1 are infrequent, they are tolerated only in the presence of p53 pathway inactivation, which would prevent senescence.
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