Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development

Malay Mandal, Sarah E. Powers, Kyoko Ochiai, Katia Georgopoulos, Barbara L. Kee, Harinder Singh, Marcus R. Clark

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Signals through the pre-B cell antigen receptor (pre-BCR) and interleukin 7 receptor (IL-7R) coordinate pre-B cell population expansion with subsequent recombination of the locus encoding immunoglobulin κ-chain (Igk). Although many 'downstream' effectors of each receptor are known, how they integrate to mediate development has remained unclear. Here we report that pre-BCR-mediated activation of the Ras-MEK-Erk signaling pathway silenced transcription of Ccnd3 (encoding cyclin D3) and coordinated exit from the cell cycle with induction of the transcription factor E2A and the initiation of Igk recombination. IL-7R-mediated activation of the transcription factor STAT5 opposed this pathway by promoting Ccnd3 expression and concomitantly inhibiting Igk transcription by binding to the Igk intronic enhancer and preventing E2A recruitment. Our data show how pre-BCR signaling poises pre-B cells to undergo differentiation after escape from IL-7R signaling.

Original languageEnglish
Pages (from-to)1110-1117
Number of pages8
JournalNature Immunology
Volume10
Issue number10
DOIs
Publication statusPublished - 2009 Sep 7
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Mandal, M., Powers, S. E., Ochiai, K., Georgopoulos, K., Kee, B. L., Singh, H., & Clark, M. R. (2009). Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development. Nature Immunology, 10(10), 1110-1117. https://doi.org/10.1038/ni.1785