MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1

Brundage, Meghan E.; Tandon, Preeti; Eaves, David W.; Williams, Jonathan; Miller, Shyra J.; Hennigan, Robert H.; Jegga, Anil G.; Cripe, Timothy P.; Ratner, Nancy

doi:10.1038/onc.2013.506

Cited by 36 publications

(28 citation statements)

References 48 publications

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“…Previous studies from our laboratories and others have shown that some signaling pathways that are involved in the myelination process (Wnt/β-catenin, mTOR, ERK) are deregulated in MPNST (12,29,30). Therefore, we inquired about the endogenous role of AHR in normal SC physiology and peripheral nerve myelination.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis

Shackleford

Sampathkumar

Hichor

et al. 2018

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

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Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in xenobiotic metabolism. Plexiform neurofibromas (PNFs) can transform into malignant peripheral nerve sheath tumors (MPNSTs) that are resistant to existing therapies. These tumors are primarily composed of Schwann cells. In addition to neurofibromatosis type 1 () gene inactivation, further genetic lesions are required for malignant transformation. We have quantified the mRNA expression levels of AHR and its associated genes in 38 human samples. We report that AHR and the biosynthetic enzymes of its endogenous ligand are overexpressed in human biopsies of PNFs and MPNSTs. We also detect a strong nuclear AHR staining in MPNSTs. The inhibition of AHR by siRNA or antagonists, CH-223191 and trimethoxyflavone, induces apoptosis in human MPNST cells. Since AHR dysregulation is observed in these tumors, we investigate AHR involvement in Schwann cell physiology. Hence, we studied the role of AHR in myelin structure and myelin gene regulation in mice during myelin development. AHR ablation leads to locomotion defects and provokes thinner myelin sheaths around the axons. We observe a dysregulation of myelin gene expression and myelin developmental markers in mice. Interestingly, AHR does not directly bind to myelin gene promoters. The inhibition of AHR in vitro and in vivo increased β-catenin levels and stimulated the binding of β-catenin on myelin gene promoters. Taken together, our findings reveal an endogenous role of AHR in peripheral myelination and in peripheral nerve sheath tumors. Finally, we suggest a potential therapeutic approach by targeting AHR in nerve tumors.

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Section: Discussionmentioning

confidence: 99%

Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis

Shackleford

Sampathkumar

Hichor

et al. 2018

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

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“…Loss of neurofibromin results in the activation of this pathway in multiple types of tumour 85,86 . Heat shock response 87 and MAF regulation of mTOR signalling 88 also occur downstream of NF1 loss and subsequent activation of ERK. RAL guanine nucleotide exchange factors have also been implicated downstream of RAS in MPNSTs 89 .…”

Section: Neurofibromin Regulation and Signallingmentioning

confidence: 99%

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

2015

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Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes affected individuals to tumours. The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies. Several RASopathies, beyond NF1, are cancer predisposition syndromes. Somatic NF1 mutations also occur in 5–10% of human sporadic cancers and may contribute to resistance to therapy. To highlight areas for investigation in RASopathies and sporadic tumours with NF1 mutations, we summarize current knowledge of NF1 disease, the NF1 gene and neurofibromin, neurofibromin signalling pathways and recent developments in NF1 therapeutics.

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“…In addition, the in situ hybridization patterns were similar to the immunohistochemistry patterns. This antibody has also been used and validated by others in both western blot and immunohistochemistry on paraffin sections (Fernandez-Saiz et al, 2013;Brundage et al, 2014).…”

Section: Antibody Characterizationmentioning

confidence: 99%

DEP domain‐containing mTOR‐interacting protein in the rat brain: Distribution of expression and potential implication

Caron

Baraboi

Laplante

et al. 2014

J of Comparative Neurology

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DEP domain-containing mTOR-interacting protein (DEPTOR) has been recently discovered as an endogenous regulator of the mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2. mTORC1 is present in the brain, and there is growing evidence that its dysregulation contributes to several brain alterations. This suggests the involvement of mTOR signaling and its modulators in neurobiological controls. Here, we characterized and mapped the expression of DEPTOR in the rat brain. We show that DEPTOR was widely expressed from the forebrain to the hindbrain, including the hippocampus, the mediobasal hypothalamus, and the circumventricular organs (CVOs). In the hippocampus, DEPTOR protein and Deptor mRNA were highly expressed in the dendate gyrus and CA3 field. In the CVOs, DEPTOR was expressed in the subfornical organ, the median eminence, and the area postrema. In the mediobasal hypothalamus, DEPTOR was expressed in neurons of the ventromedial nucleus (VMH) and colocalized with proopiomelanocortin (POMC) in the arcuate nucleus (ARC). The hypothalamic distribution suggested a role for DEPTOR in energy balance. Supporting this possibility, we observed that Deptor hypothalamic expression was modulated by the nutritional status in a context of diet-induced and genetic obesity; food deprivation increased Deptor mRNA in both the ARC and VMH of obese rats. In conclusion, the present results illustrate the presence of DEPTOR in the rat brain and suggest a role for DEPTOR in the hypothalamic regulation of energy balance, which further supports the role of mTOR in energy homeostasis. J. Comp. Neurol. 523:93-107, 2015. © 2014 Wiley Periodicals, Inc.

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MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1

Cited by 36 publications

References 48 publications

Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis

Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

DEP domain‐containing mTOR‐interacting protein in the rat brain: Distribution of expression and potential implication

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