Ras mediates effector pathways responsible for pre-B cell survival, which is essential for the developmental progression to the late pre-B cell stage.
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.
Nagaoka
H
H
Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Takahashi
Y
Y
Hayashi
R
R
Nakamura
T
T
Ishii
K
K
Matsuda
J
J
Ogura
A
A
Shirakata
Y
Y
Karasuyama
H
H
Sudo
T
T
Nishikawa
S
S
Tsubata
T
T
Mizuochi
T
T
Asano
T
T
Sakano
H
H
Takemori
T
T
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
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)