Hematologic effects of inactivating the Ras processing enzyme Rce1

Abstract

Posttransiational processing of Ras proteins has attracted considerable interest as a potential target for anticancer drug discovery. Rcel 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 Rcel 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 granulocytemacrophage colony-stimulating factor. These data suggest that pharmacologic inhibitors of Rce1 will have minimal effects on normal hematopoietic cells. © 2003 by The American Society of Hematology.