The Journal of Experimental Medicine
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Published online 17 July 2000.
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© The Rockefeller University Press, 0022-1007/2000/7/171/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 2, July 17, 2000 171-182

Original Article

Ras Mediates Effector Pathways Responsible for Pre-B Cell Survival, Which Is Essential for the Developmental Progression to the Late Pre-B Cell Stage

Hitoshi Nagaokaa, Yoshimasa Takahashia, Reiko Hayashid, Tohru Nakamuraa,e, Kumiko Ishiia, Junichiro Matsudab, Atsuo Ogurab, Yumiko Shirakataf, Hajime Karasuyamag, Tetsuo Sudoh, Shin-Ichi Nishikawai, Takeshi Tsubataj, Tsuguo Mizuochie, Toshihiko Asanoc, Hitoshi Sakanod, and Toshitada Takemoria

a Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
b Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
c Division of Experimental Animal Research, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
d Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan
e Laboratory of Biomedical Chemistry, Department of Applied Chemistry, Tokai University, Kanagawa 259-1292, Japan
f Department of Gene Research, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan
g Department of Immunology, The Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan
h Toray Basic Research Laboratories, Kanagawa-ken 259-1192, Japan
i Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
j Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-Ku, Tokyo 162-8640, Japan.81-3-5285-115681-3-5285-1156

ttoshi{at}nih.go.jp

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 p21ras 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 p21Asn-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 p21ras 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 p21ras 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 p21ras mediates effector pathways responsible for pre-B cell survival, which is essential for progression to the late pre-B and immature B stages.

Key Words: B cell development • life span • immunoglobulin gene rearrangement • Bcl-xL • Bcl-2

Abbreviations used in this paper: APC, allophycocyanin; BLNK, B cell linker protein; BM, bone marrow; BrdU, bromodeoxyuridine; EMA, ethidium monoazide; ERK, extracellular signal–regulated kinase; 3' E{kappa}, 3' Ig{kappa} enhancer; Eµ, IgH intronic enhancer; HSA, heat-stable antigen; LM, littermate controls; MAP, mitogen-activated protein; PI-3K, phosphatidylinositol 3-kinase; pre-BCR, pre-B cell antigen receptor; RT, reverse transcription; sIg, surface Ig; SL, surrogate L chain; TG, transgenic mice.

H. Nagaoka and Y. Takahashi contributed equally to this work.

H. Nagaoka's current address is Laboratory of Molecular Immunology, The Rockefeller University, 1230 York Ave., New York, NY 10021.

© 2000 The Rockefeller University Press


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