Aberrant cAMP Metabolism in NF1 Malignant Peripheral Nerve Sheath Tumor Cells

Dang, Ian; Vries, George H. De

doi:10.1007/s11064-011-0433-2

Cited by 16 publications

(11 citation statements)

References 40 publications

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“…Those studies pointed to misregulation of several important downstream signaling pathways, including the MEK/MAPK and cAMP-mediated PKA pathways; however, depending on the cell type analyzed, either up-or down-regulation of cAMP content was correlated with decreased expression of neurofibromin. Thus, Schwann cells retrieved from neurofibromas exhibited increased cAMP levels (30,35). Activation of MEK/MAPK was also observed in the peripheral nerve sheath in one mouse model (36).…”

Section: Discussionmentioning

confidence: 88%

“…To decipher the molecular mechanisms linking down-expression of neurofibromin with the hyperpigmentation phenotype, we focused our attention on a possible role of cAMP-mediated PKA and ERK signaling pathways, which have been shown to be misregulated in various NF1 models (10,29,30). ELISA revealed a fourfold increase in cAMP levels in mel-NF1 cells compared with mel-WT cells (Fig.…”

Section: Nf1 Hescs-derived Melanocytes Phenocopied the Hyperpigmentationmentioning

confidence: 99%

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In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

Allouche

Bellon

Saidani

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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"Café-au-lait" macules (CALMs) and overall skin hyperpigmentation are early hallmarks of neurofibromatosis type 1 (NF1). One of the most frequent monogenic diseases, NF1 has subsequently been characterized with numerous benign Schwann cell-derived tumors. It is well established that neurofibromin, the NF1 gene product, is an antioncogene that down-regulates the RAS oncogene. In contrast, the molecular mechanisms associated with alteration of skin pigmentation have remained elusive. We have reassessed this issue by differentiating human embryonic stem cells into melanocytes. In the present study, we demonstrate that NF1 melanocytes reproduce the hyperpigmentation phenotype in vitro, and further characterize the link between loss of heterozygosity and the typical CALMs that appear over the general hyperpigmentation. Molecular mechanisms associated with these pathological phenotypes correlate with an increased activity of cAMP-mediated PKA and ERK1/2 signaling pathways, leading to overexpression of the transcription factor MITF and of the melanogenic enzymes tyrosinase and dopachrome tautomerase, all major players in melanogenesis. Finally, the hyperpigmentation phenotype can be rescued using specific inhibitors of these signaling pathways. These results open avenues for deciphering the pathological mechanisms involved in pigmentation diseases, and provide a robust assay for the development of new strategies for treating these diseases.neurofibromatosis type 1 | melanocytes | embryonic stem cells | hyperpigmentation | disease modeling

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Section: Discussionmentioning

confidence: 88%

Section: Nf1 Hescs-derived Melanocytes Phenocopied the Hyperpigmentationmentioning

confidence: 99%

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

Allouche

Bellon

Saidani

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…3) and it is not clear what neurofibromin domains mediate these effects. There is evidence that that neurofibromin alters cAMP levels in astrocytes [37], non-neoplastic Schwann cells [85] and neoplastic Schwann cells [35], thereby regulating cAMP-dependent signaling pathways. Interestingly, neurofibromin loss increases cAMP levels in Schwann cells while decreasing them in astrocytes; these respective changes are both likely to be pro-proliferative.…”

Section: Neurofibromas and Mpnstsmentioning

confidence: 99%

Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms

Carroll

2011

Acta Neuropathol

106

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Neurofibromas, schwannomas and malignant peripheral nerve sheath tumors (MPNSTs) all arise from the Schwann cell lineage. Despite their common origin, these tumor types have distinct pathologies and clinical behaviors; a growing body of evidence indicates that they also arise via distinct pathogenic mechanisms. Identification of the genes that are mutated in genetic diseases characterized by the development of either neurofibromas and MPNSTs [neurofibromatosis type 1 (NF1)] or schwannomas [neurofibromatosis type 2 (NF2), schwannomatosis and Carney complex type 1] has greatly advanced our understanding of these mechanisms. The development of genetically engineered mice with ablation of NF1, NF2, SMARCB1/INI1 or PRKAR1A has confirmed the key role these genes play in peripheral nerve sheath tumorigenesis. Establishing the functions of the NF1, NF2, SMARCB1/INI1 and PRKAR1A gene products has led to the identification of key cytoplasmic signaling pathways promoting Schwann cell neoplasia and identified new therapeutic targets. Analyses of human neoplasms and genetically engineered mouse models have established that interactions with other tumor suppressors such as TP53 and CDKN2A promote neurofibroma-MPNST progression and indicate that intratumoral interactions between neoplastic and non-neoplastic cell types play an essential role in peripheral nerve sheath tumorigenesis. Recent advances have also provided new insights into the identity of the neural crest-derived populations that give rise to different types of peripheral nerve sheath tumors. Based on these findings, we now have an initial outline of the molecular mechanisms driving the pathogenesis of neurofibromas, MPNSTs and schwannomas. However, this improved understanding in turn raises a host of intriguing new questions.

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“…Finally, neurofibromin modulates cAMP levels. Curiously, neurofibromin effects on cAMP levels are cell-type dependent, as neurofibromin loss elevates cAMP levels in Schwann cells [18, 38] and reduces them in astrocytes [20]. The mechanism responsible for these effects is unknown.…”

Section: Pathology Of Human Peripheral Nerve Sheath Tumors and Thementioning

confidence: 99%

Genetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system

Brossier

Carroll

2012

Brain Research Bulletin

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Neurofibromatosis type 1 (NF1), the most common genetic disorder affecting the human nervous system, is characterized by the development of multiple benign Schwann cell tumors in skin and large peripheral nerves. These neoplasms, which are termed dermal and plexiform neurofibromas respectively, have distinct clinical courses; of particular note, plexiform, but not dermal, neurofibromas often undergo malignant progression to form malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy occurring in NF1 patients. In recent years, a number of genetically engineered mouse models have been created to investigate the molecular mechanisms driving the pathogenesis of these tumors. These models have been designed to address key questions including: 1) whether NF1 loss in the Schwann cell lineage is essential for tumorigenesis; 2) what cell type(s) in the Schwann cell lineage gives rise to dermal neurofibromas, plexiform neurofibromas and MPNSTs; 3) how the tumor microenvironment contributes to neoplasia; 4) what additional mutations contribute to neurofibroma-MPNST progression; 5) what role different neurofibromin-regulated Ras proteins play in this process and 6) how dysregulated growth factor signaling facilitates PNS tumorigenesis. In this review, we summarize the major findings from each of these models and their limitations as well as how discrepancies between these models may be reconciled. We also discuss how information gleaned from these models can be synthesized to into a comprehensive model of tumor formation in peripheral nervous system and consider several of the major questions that remain unanswered about this process.

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Aberrant cAMP Metabolism in NF1 Malignant Peripheral Nerve Sheath Tumor Cells

Cited by 16 publications

References 40 publications

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms

Genetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system

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