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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA074177-02
Application #
2683711
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mufson, R Allan
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202