Hematologic effects of inactivating the Ras processing enzyme Rce1.
Posttranslational processing of Ras proteins has attracted considerable interest as a potential target for anticancer drug discovery. Rce1 encodes an endoprotease that facilitates membrane targeting of Ras and other prenylated proteins by releasing the carboxyl-terminal 3 amino acids (ie, the -AAX of the CAAX motif). Homozygous Rce1 mutant embryos (Rce1(-/-)) die late in gestation. To characterize the role of Rce1 in hematopoiesis, we performed adoptive transfers and investigated cells from the recipients. Rce1(-/-) fetal liver cells rescued lethally irradiated recipients and manifested normal long-term repopulating potential in competitive repopulation assays. The recipients of Rce1(-/-) cells developed modest elevations in mature myeloid cells (neutrophils + monocytes), but remained well. Bone marrow cells from mice that received transplants of Rce1(-/-) activated extracellular signal-related kinase (ERK) normally in response to granulocyte-macrophage colony-stimulating factor. These data suggest that pharmacologic inhibitors of Rce1 will have minimal effects on normal hematopoietic cells.
Aiyagari
Abigail L
AL
Department of Pediatrics, Gladstone Institute of Cardiovascular Disease, University of California, San Francisco (UCSF), CA 94143, USA.
Taylor
Brigit R
BR
Aurora
Vikas
V
Young
Stephen G
SG
Shannon
Kevin M
KM
D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology; D010450:Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation; D006579:Heterozygote; D007958:Leukocyte Count; D008099:Liver / Q000166:cytology / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation
D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D010450:Endopeptidases; C491324:Rce1 protein, mouse