Neurofibromin regulates G protein–stimulated adenylyl cyclase activity

Tong, Jiayuan; Hannan, Frances; Zhu, Yingting; Bernards, André; Zhong, Yi

doi:10.1038/nn792

Cited by 231 publications

(189 citation statements)

References 14 publications

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“…Previous studies from our laboratory and others have shown that neurofibromin positively regulates cyclic adenosine monophosphate (cAMP) levels (Tong et al, 2002;Dasgupta et al, 2003) in the brain in addition to negatively regulating Ras activity. The regulation of both Ras and cAMP is one of the properties of G-protein-coupled receptors, which suggests that chemokines present in the tumor microenvironment might increase Nf1 À/À astrocyte growth.…”

Section: Stromal Determinants Of Glioma Formation and Growthmentioning

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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Section: Stromal Determinants Of Glioma Formation and Growthmentioning

confidence: 99%

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

Pong

Gutmann

2010

Oncogene

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“…A functional GAP domain encoded within neurofibromin attenuates Ras function by rapidly converting active GTP-Ras to the inactive GDP form (Adjei, 2001). As a result, a number of laboratories have undertaken studies to address the specific involvement of neurofibromin in the posttranslational regulation of Ras and downstream MAP kinase and adenylyl cyclase pathways (Kim et al, 2001;Tong et al, 2002). In contrast, a basic understanding of the transcriptional regulation of the NF1 gene is limited.…”

Section: Introductionmentioning

confidence: 99%

Characterization of functional elements in the neurofibromatosis (NF1) proximal promoter region

et al. 2004

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An essential requirement to understand how genes contribute to genetic disease is the thorough knowledge of the transcriptional regulation of gene expression. Here, we have characterized transcription factor binding sites within the type 1 neurofibromatosis (NF1) proximal regulatory region, and addressed the molecular mechanisms that regulate NF1 transcription. Overlapping regions of the NF1 proximal promoter have been cloned and characterized for use in luciferase reporter assays. These assays have identified a 500 bp region displaying activities up to 80-fold higher than control reporter levels. Mutations at putative CRE and SP1-binding sites immediately 5 0 to the transcription start site have dramatic effects that lead to a 70-90% decrease in reporter activity in all cell lines tested. Gelshift assays confirm binding of CREB and SP1/KLF family members to their putative recognition sequences, and provide the first evidence identifying functional sites likely involved in regulating NF1 transcription. These assays have also revealed a putative repressor region within the NF1 promoter region corresponding to CCCTC-rich sequences between the transcription and translation start sites. This work provides new information concerning the transcriptional regulation of the NF1 gene, and is the most thorough attempt to date to map functionally relevant regions within the NF1 proximal promoter region.

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“…Neurofibromin down-regulates RAS signaling by accelerating the conversion of active RAS-guanosine triphosphate (GTP) to inactive RAS-guanosine diphosphate (GDP) (8,9). The resulting decreased expression of neurofibromin leads to activation of several important downstream signaling pathways, including mitogen extracellular signal-regulated Kinase (MEK)/mitogen activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP)-mediated protein kinase A (PKA) pathways (10,11). Just how these defects in multiple signaling pathways cause the specific alterations of pigmentation originally observed in patients is not yet clear.…”

mentioning

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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"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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Neurofibromin regulates G protein–stimulated adenylyl cyclase activity

Cited by 231 publications

References 14 publications

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

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

Characterization of functional elements in the neurofibromatosis (NF1) proximal promoter region

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

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