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

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.
Authors	M E Brundage, P Tandon, D W Eaves, J P Williams, S J Miller, R H Hennigan, A Jegga, T P Cripe, N Ratner
Journal	Oncogene (Oncogene) Vol. 33 Issue 49 Pg. 5626-36 (Dec 04 2014) ISSN: 1476-5594 [Electronic] England
PMID	24509877 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	MAF protein, human Neurofibromin 1 Proto-Oncogene Proteins c-maf MTOR protein, human TOR Serine-Threonine Kinases ras Proteins
Topics	Animals Cell Differentiation Down-Regulation Female Gene Expression Regulation, Neoplastic Genes, Neurofibromatosis 1 Humans MAP Kinase Signaling System Mice Mice, Nude Neoplasm Transplantation Nerve Sheath Neoplasms (genetics, metabolism) Neurofibromatosis 1 (genetics, metabolism) Neurofibromin 1 (metabolism) Neuroglia (metabolism) Oligonucleotide Array Sequence Analysis Phenotype Proto-Oncogene Proteins c-maf (physiology) Schwann Cells (cytology) Signal Transduction TOR Serine-Threonine Kinases (metabolism) Transcriptome ras Proteins (metabolism)

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