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

Oncogene volume 33, pages 5626–5636 (2014)Cite this article

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Abstract

Mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene are common in cancer and can cause resistance to therapy. Using transcriptome analysis we identified MAF as an NF1- regulated transcription factor and verified MAF regulation through RAS/MAPK/AP-1 signaling in malignant peripheral nerve sheath tumor (MPNST) cell lines. MAF was also downregulated in human MPNST. Acute re-expression of MAF promoted expression of glial differentiation markers in MPNST cells in vitro, decreased self-renewal of embryonic precursors and transiently affected tumor cell phenotypes in vitro by increasing MPNST cell death and reducing metabolic activity and anchorage-independent growth. Paradoxically, chronic MAF overexpression enhanced MPNST cell tumor growth in vivo, correlating with elevated pS6 in vitro and in vivo. RAD001 blocked MAF-mediated tumor growth, and MAF regulated the mTOR pathway through DEPTOR. MAPK inhibition with NF1 loss of function is predicted to show limited efficacy due to reactivation of mTOR signaling via MAF.

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Acknowledgements

We thank Frank McCormick (UCSF) for providing NF1 constructs and Kohsuke Kataoka for providing the MAF reporter. We thank the Viral Vector Core in the Translational Core Laboratories at Cincinnati Children’s Hospital Medical Center for viral vector production. We thank Monica DeLay for assistance with flow cytometry from the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children’s Hospital Medical Center, supported in part by NIH AR-47363, NIH DK78392 and NIH DK90971. This work was supported by R01 NS28840 (to NR) and NIH-P50-NS057531 (to NR and TPC). MB was partially supported by a training grant, T32HD07463.

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Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, University of Cincinnati College of Medicine, OH, Cincinnati, USA

    M E Brundage, P Tandon, D W Eaves, J P Williams, S J Miller, R H Hennigan & N Ratner

  2. Division Biomedical Informatics, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, OH, Cincinnati, USA

    A Jegga

  3. Division of Oncology, Department of Pediatrics, University of Cincinnati College of Medicine, OH, Cincinnati, USA

    T P Cripe

  4. Division of Hematology/Oncology/BMT, Nationwide Children’s Hospital, The Ohio State University, OH, Columbus, USA

    T P Cripe

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Correspondence to N Ratner.

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Brundage, M., Tandon, P., Eaves, D. et al. MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1. Oncogene 33, 5626–5636 (2014). https://doi.org/10.1038/onc.2013.506

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