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

doi:10.1084/jem.192.2.171

Published online 10 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 Nagaoka^a, Yoshimasa Takahashi^a, Reiko Hayashi^d, Tohru Nakamura^a,e, Kumiko Ishii^a, Junichiro Matsuda^b, Atsuo Ogura^b, Yumiko Shirakata^f, Hajime Karasuyama^g, Tetsuo Sudo^h, Shin-Ichi Nishikawaⁱ, Takeshi Tsubata^j, Tsuguo Mizuochi^e, Toshihiko Asano^c, Hitoshi Sakano^d, and Toshitada Takemori^a
^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

Correspondence to: Toshitada Takemori, Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-Ku, Tokyo 162-8640, Japan. Tel:81-3-5285-1156 Fax:81-3-5285-1156 E-mail:ttoshi{at}nih.go.jp.

Ras is essential for the transition from early B cell precursorsto the pro-B stage, and is considered to be involved in thesignal cascade mediated by pre-B cell antigen receptors. Toexamine the role of p21^ras in the late stage of B cell differentiation,we established transgenic mice (TG) expressing a dominant-inhibitorymutant of Ha-ras (Asn-17 Ha-ras) in B lineage cells at highlevels after the early B cell precursor stage. Expression ofp21^Asn-17 ^Ha-ras was associated with a prominent reduction inthe number of late pre-B cells, but had little effect on proliferationof early pre-B cells. Inhibition of p21^ras activity markedlyreduced 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-Bcell survival may explain the decreased numbers of late pre-Bcells in Asn-17 Ha-ras TG. Consistent with this possibility,overexpression of Bcl-2 in Asn-17 Ha-ras TG reversed the reductionin the number of late pre-B cells undergoing immunoglobulinlight chain gene (IgL) rearrangement and progressing to immatureB cells. These results suggest that p21^ras mediates effectorpathways responsible for pre-B cell survival, which is essentialfor progression to the late pre-B and immature B stages.

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

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