title: 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: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: M E
authors: ME
authors: Brundage
authors: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: P
authors: P
authors: Tandon
authors: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: D W
authors: DW
authors: Eaves
authors: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: J P
authors: JP
authors: Williams
authors: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: S J
authors: SJ
authors: Miller
authors: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: R H
authors: RH
authors: Hennigan
authors: Division Biomedical Informatics, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: A
authors: 0000000248817752
authors: A
authors: Jegga
authors: 1] Division of Oncology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA [2] Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors: T P
authors: TP
authors: Cripe
authors: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: N
authors: N
authors: Ratner
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018317:Nerve Sheath Neoplasms / Q000235:genetics* / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism; D025542:Neurofibromin 1 / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051257:Proto-Oncogene Proteins c-maf / Q000502:physiology*; D012583:Schwann Cells / Q000166:cytology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D059467:Transcriptome; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C495607:MAF protein, human; D025542:Neurofibromin 1; D051257:Proto-Oncogene Proteins c-maf; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins