The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

S. Shapira, B. Barkan, E. Fridman, Y. Kloog, R. Stein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Neurofibromatosis type 1 (NF1) is characterized by a high incidence of benign and malignant tumors attributed to loss of function of Nf1, which encodes neurofibromin, a tumor suppressor with Ras-GAP activity. Neurofibromin deficiency typically causes chronic activation of Ras, considered the major contributor to manifestation of NF1. Resistance to radio- and chemotherapy are typical of NF1-associated tumors, but the underlying mechanism is unknown. Here, we investigated interrelationships between neurofibromin expression, Ras activity, and sensitivity to apoptosis. Neurofibromin-deficient mouse embryonic fibroblasts (MEFs) and human NF1 tumor cells were more resistant than neurofibromin-expressing cells to apoptosis. Moreover, Nf1-/-, Nf1+/-, and Nf1+/+ MEFs exhibited gene-dosage-related resistance to apoptosis. Resistance of the Nf1-deficient cells was mediated by two survival pathways: a Ras-dependent pathway, and a Ras-independent pathway promoted by the lack of an NF1-GRD-independent proapoptotic action of neurofibromin. Therefore, besides its Ras-dependent growth inhibition, neurofibromin can exert tumor suppression via a proapoptotic effect.

Original languageEnglish
Pages (from-to)895-906
Number of pages12
JournalCell Death and Differentiation
Volume14
Issue number5
DOIs
StatePublished - May 2007

Funding

FundersFunder number
Israel Ministry of Health
Recanati Foundation for Research in Medicine
U.S. Department of DefenseNF 030009

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