Molecular and Cellular Biochemistry

, Volume 344, Issue 1–2, pp 267–276

The role of neurofibromin in N-Ras mediated AP-1 regulation in malignant peripheral nerve sheath tumors

  • Janice M. Kraniak
  • Daochun Sun
  • Raymond R. Mattingly
  • John J. ReinersJr.
  • Michael A. Tainsky
Article

Abstract

Plexiform neurofibromas commonly found in patients with Neurofibromatosis type I (NF1) have a 5% risk of being transformed into malignant peripheral nerve sheath tumors (MPNST). Germline mutations in the NF1 gene coding for neurofibromin, which is a Ras GTPase activating protein (RasGAP) and a negative regulator of Ras, result in an upregulation of the Ras pathway. We established a direct connection between neurofibromin deficiency and downstream effectors of Ras in cell lines from MPNST patients by demonstrating that knockdown of NF1 expression using siRNA in a NF1 wild type MPNST cell line, STS-26T, activates the Ras/ERK1,2 pathway and increases AP-1 binding and activity. We believe this is the first time the transactivation of AP-1 has been linked directly to neurofibromin deficiency in a disease relevant MPNST cell line. Previously, we have shown that N-Ras is constitutively activated in cell lines derived from independent MPNSTs from NF1 patients. We therefore sought to analyze the role of the N-Ras pathway in deregulating AP-1 transcriptional activity. We show that STS-26T clones conditionally expressing oncogenic N-Ras show increased phosphorylated ERK1,2 and phosphorylated JNK expression concomitant with increased AP-1 activity. MAP kinase pathways (ERK1,2 and JNK) were further examined in ST88-14, a neurofibromin-deficient MPNST cell line. The basal activity of ERK1,2 but not JNK was found to increase AP-1 activity. These experiments further confirmed the link between the loss of neurofibromin and increased activity of Ras/MAP kinase pathways and the activation of downstream transcriptional mechanisms in MPNSTs from NF1 patients.

Keywords

Neurofibromin (NF1) Activating protien 1 (AP-1) N-Ras oncogene Extracellular signal-regulated kinase (ERK) c-Jun N-terminal kinase (JNK) 

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Janice M. Kraniak
    • 1
  • Daochun Sun
    • 3
  • Raymond R. Mattingly
    • 1
    • 4
    • 6
  • John J. ReinersJr.
    • 2
    • 4
    • 5
    • 6
  • Michael A. Tainsky
    • 1
    • 3
    • 6
    • 7
  1. 1.Programs in Molecular Biology and GeneticsBarbara Ann Karmanos Cancer InstituteDetroitUSA
  2. 2.Programs in ProteasesBarbara Ann Karmanos Cancer InstituteDetroitUSA
  3. 3.Center for Molecular Medicine and GeneticsWayne State University School of MedicineDetroitUSA
  4. 4.Department of PharmacologyWayne State University School of MedicineDetroitUSA
  5. 5.Institute of Environmental Health SciencesWayne State University School of MedicineDetroitUSA
  6. 6.Environmental Health Sciences Center for Molecular and Cellular Toxicology with Human ApplicationsWayne State University School of MedicineDetroitUSA
  7. 7.Department of PathologyWayne State University School of MedicineDetroitUSA

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