NEUROFIBROMATOSIS TYPE 1 GENE REGULATES MYELOPOIESIS

Project: Research project

Description

DESCRIPTION: The proteins encoded by the p21ras (Ras) family of protooncogenes control cellular growth and differentiation by cycling between an active guanosine triphosphate (GTP)-bound state and an inactive guanosine diphosphate (GDP)-bound state. Mammalian GTPase activating proteins (GAPs) regulate Ras proteins by accelerating GTP hydrolysis. Neurofibromin, the 327 kD protein product of the NF1 gene, contains domains that are homologous to mammalian and yeast GAPs, bind to Ras proteins with high affinity, and promotes the conversion of Ras-GTP to Ras-GDP at physiologic concentrations. Mutations in NF1 cause the common genetic disorder neurofibromatosis, type 1 (NF1) which is associated with a predisposition to neural crest derived tumors and juvenile chronic myelogenous leukemia (JCML). These observations led to the proposal that NF1 functions as a tumor suppressor gene by negatively regulating Ras-GTP. Clinical, genetic, and biochemical data from studies of hematopoietic cells strongly support this hypothesis. The Investigators have developed a murine model to investigate the role of the murine homologue of NF1 in myeloid and stem cell control. Their laboratory has shown that hematopoietic cells from embryos that are homozygous for a targeted disruption of NF1 have a selective and enhanced sensitivity to GM-CSF in a myeloid progenitor assay that is remarkably similar to the pattern observed in patients with juvenile chronic myelogenous leukemia. Together with their collaborators, they have demonstrated that the absence of the NF1 gene in fetal liver hematopoietic cells also resulted in aberrant Ras signaling. The goals of this proposal are to investigate the cellular physiology and molecular mechanisms that underlay how NF1 regulated the proliferation and differentiation of hematopoietic progenitor and stem cell populations in vitro and in vivo.
StatusFinished
Effective start/end date4/1/972/28/14

Funding

  • National Institutes of Health
  • National Institutes of Health: $324,865.00
  • National Institutes of Health: $325,689.00
  • National Institutes of Health: $44,888.00
  • National Institutes of Health: $310,959.00
  • National Institutes of Health: $312,768.00
  • National Institutes of Health: $105,000.00
  • National Institutes of Health: $338,107.00
  • National Institutes of Health: $333,781.00
  • National Institutes of Health: $314,738.00
  • National Institutes of Health: $484,270.00
  • National Institutes of Health: $498,147.00
  • National Institutes of Health: $331,525.00
  • National Institutes of Health: $105,000.00
  • National Institutes of Health: $135,113.00

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Neurofibromatosis 1 Genes
Myelopoiesis
Neurofibromatosis 1
Neurofibromin 1
Proto-Oncogene Proteins p21(ras)
Mast Cells
Plexiform Neurofibroma
Juvenile Myelomonocytic Leukemia
Guanosine Triphosphate
Haploinsufficiency
GTPase-Activating Proteins
Tumor Suppressor Genes
Granulocyte-Macrophage Colony-Stimulating Factor
Tumor Microenvironment
Myeloid Progenitor Cells
ras Proteins
Granulocyte-Macrophage Progenitor Cells
Mutation
Guanosine
Inborn Genetic Diseases

ASJC

  • Medicine(all)