title: Ras mediates effector pathways responsible for pre-B cell survival, which is essential for the developmental progression to the late pre-B cell stage.
abstract: Ras is essential for the transition from early B cell precursors to the pro-B stage, and is considered to be involved in the signal cascade mediated by pre-B cell antigen receptors. To examine the role of p21(ras) in the late stage of B cell differentiation, we established transgenic mice (TG) expressing a dominant-inhibitory mutant of Ha-ras (Asn-17 Ha-ras) in B lineage cells at high levels after the early B cell precursor stage. Expression of p21(Asn-17) (Ha-ras) was associated with a prominent reduction in the number of late pre-B cells, but had little effect on proliferation of early pre-B cells. Inhibition of p21(ras) activity markedly reduced the life span of pre-B cells, due, at least in part, to downregulation of the expression of an antiapoptotic protein, Bcl-xL. Thus, the apparent role for p21(ras) activity in pre-B cell survival may explain the decreased numbers of late pre-B cells in Asn-17 Ha-ras TG. Consistent with this possibility, overexpression of Bcl-2 in Asn-17 Ha-ras TG reversed the reduction in the number of late pre-B cells undergoing immunoglobulin light chain gene (IgL) rearrangement and progressing to immature B cells. These results suggest that p21(ras) mediates effector pathways responsible for pre-B cell survival, which is essential for progression to the late pre-B and immature B stages.
authors.affiliation: Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nagaoka
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: R
authors.initials: R
authors.lastname: Hayashi
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Ishii
authors.forename: J
authors.initials: J
authors.lastname: Matsuda
authors.forename: A
authors.initials: A
authors.lastname: Ogura
authors.forename: Y
authors.initials: Y
authors.lastname: Shirakata
authors.forename: H
authors.initials: H
authors.lastname: Karasuyama
authors.forename: T
authors.initials: T
authors.lastname: Sudo
authors.forename: S
authors.initials: S
authors.lastname: Nishikawa
authors.forename: T
authors.initials: T
authors.lastname: Tsubata
authors.forename: T
authors.initials: T
authors.lastname: Mizuochi
authors.forename: T
authors.initials: T
authors.lastname: Asano
authors.forename: H
authors.initials: H
authors.lastname: Sakano
authors.forename: T
authors.initials: T
authors.lastname: Takemori
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001854:Bone Marrow Cells / Q000502:physiology; D002470:Cell Survival; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000502:physiology*; D019076:Transgenes; D051020:bcl-X Protein
chemical_list: C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)