The NF1 tumor suppressor critically regulates TSC2 and mTOR

Johannessen, Cory M.; Reczek, Elizabeth E.; James, Marianne F.; Brems, Hilde; Legius, Eric; Cichowski, Karen

doi:10.1073/pnas.0503224102

Cited by 532 publications

(432 citation statements)

References 45 publications

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“…Furthermore, their signaling properties were consistent with those reported for their corresponding primary MEFs. 23,24 Accordingly, the steady-state levels of Ras-GTP, phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated Akt/PKB, and phosphorylated mTOR in SV40 MEFs grown in 0.5% serum (hereafter termed serum-starved cells) were significantly higher in the Nf1 À/À than in the Nf1 þ / þ genotype ( Figure 1a (Figure 1c). Thus, the three Nf1 SV40 MEF genotypes had retained the signaling properties of their primary MEF counterparts and could therefore be considered a suitable model system.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2006

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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 À/À , Nf1 þ /À , and Nf1 þ / þ 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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2006

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“…Indeed, the simultaneous activation and intrafamily functional redundancy of Ras proteins in NF1-null MPNST cells suggests that it will be difficult to target these proteins therapeutically. Consequently, some laboratories have asked whether targeting signaling pathways downstream of Ras such as mitogen-activated protein extracellular signal-related kinase (ERK) kinase (MEK) 31,32 and the phosphatidylinositol 3-kinase (PI3K)-Akt-TSC2-mammalian target of rapamycin (mTOR)-S6 kinase 33,34 would be more effective therapeutically. Although initial results indicate that this is the case, note that the full repertoire of Ras-dependent signaling pathways activated in NF1-null peripheral nerve sheath tumors has not yet been defined.…”

Section: Oncogenomics In Mpnst Modelsmentioning

confidence: 99%

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

Carroll

2016

The American Journal of Pathology

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Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cellederived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1eassociated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell-autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16 INK4A -cyclin D1-CDK4-Rb and p19 ARF -Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis. (Am J Pathol 2016, 186: 464e477; http://dx

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“…Multiple pathways contribute to increased osteoclast activity and gain of function (Yang et al, 2006; Yan et al, 2008;Li et al, 2009) as well as abnormal myeloid cell survival and proliferation (Bollag et al, 1996;Donovan et al, 2002). However, Nf1-deficient cell growth regulation is dependent on Ras activation of the mammalian target of rapamycin (mTOR) pathway in astrocytes (Dasgupta et al, 2005b;Sandsmark et al, 2007) and Schwann cells (Johannessen et al, 2005;Johansson et al, 2008). In astrocytes, neurofibromin loss leads to mTOR-dependent increases in cell proliferation, which reflect mTOR regulation of Rac1 (Sandsmark et al, 2007) and STAT3 (Banerjee et al, 2010).…”

Section: Susceptible Cell Typementioning

confidence: 99%

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

Pong

Gutmann

2010

Oncogene

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Traditionally, cancer studies have primarily focused on mutations that activate growth or survival pathways in susceptible pre-neoplastic/neoplastic cells. However, recent research has revealed a critical role for nonneoplastic cells within the tumor microenvironment in the process of cancer formation and progression. In addition, the existence of regional and developmental variations in susceptible cell types and supportive microenvironments support a model of tumorigenesis in which the dynamic symbiotic relationship between neoplastic and non-neoplastic cell types dictate where and when cancers form and grow. In this review, we highlight advances in neurofibromatosis type 1 (NF1) genetically engineered mouse brain tumor (glioma) modeling to reveal how cellular and molecular heterogeneity in both the pre-neoplastic/ neoplastic and non-neoplastic cellular compartments contribute to gliomagenesis and glioma growth.

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The NF1 tumor suppressor critically regulates TSC2 and mTOR

Abstract: CorrectionsCELL BIOLOGY. For the article ''The NF1 tumor suppressor critically regulates TSC2 and mTOR,''

Cited by 532 publications

References 45 publications

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

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

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

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

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