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  • Original Paper
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BCR signals target p27Kip1 and cyclin D2 via the PI3-K signalling pathway to mediate cell cycle arrest and apoptosis of WEHI 231 B cells

Oncogene volume 20, pages 7352–7367 (2001)Cite this article

Abstract

Cross-linking of the B cell antigen receptor (BCR) on immature WEHI 231 B cells results in G1 cell cycle arrest and apoptosis. Here we investigated the molecular mechanisms that are necessary and sufficient for these changes to occur. We show that BCR stimulation of WEHI 231 cells results in down-regulation of cyclin D2 and up-regulation of p27Kip1, which are associated with pocket protein hypophosphorylation and E2F inactivation. Ectopic expression of p27Kip1 by TAT-fusion protein or retroviral transduction is sufficient to cause G1 cell cycle arrest, followed by apoptosis. In contrast, over-expression of cyclin D2 overcomes the cell cycle arrest and apoptosis induced by anti-IgM, indicating that down-regulation of cyclin D2 is necessary for the cell cycle arrest and apoptosis activated by BCR stimulation. Thus, cyclin D2 and p27Kip1 have opposing roles in these pathways and our data also suggest that cyclin D2 functions upstream of p27Kip1 and the pRB pathway and therefore plays an essential part in integrating the signals from BCR with the cell cycle machinery. We next investigated which signal transduction pathways triggered by the BCR regulate cell proliferation and apoptosis via cyclin D2 and p27Kip1. Inhibition of PI3-K signalling by LY294002 down-regulated cyclin D2 and up-regulated p27Kip1 expression at both protein and RNA levels, mimicking the effects of BCR-stimulation. Furthermore, ectopic expression of a constitutively active form of AKT blocked the cell cycle arrest and apoptosis triggered by anti-IgM and also abrogated down-regulation of cyclin D2 and up-regulation of p27Kip1 expression induced by BCR-engagement. These results indicate that BCR activation targets p27Kip1 and cyclin D2 to mediate cell cycle arrest and apoptosis and that down-regulation of PI3-K/AKT activity post BCR stimulation is necessary for these to occur.

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Acknowledgements

We acknowledge the generosity of Dr Charles Sherr for the mouse cyclin D2 and p27Kip1 cDNAs. We also thank Dr S Dowdy for TAT-fusion constructs and protocols. The work of Eric Lam, Janet Glassford, and Shaun Thomas are also supported by the Leukaemia Research Fund. Shaun Thomas and Nicholas Lea are funded by the Sir Charles Wolfson Trust. Lolita Banerji is funded by the University of London Trust Postgraduate Studentship.

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research and Section of Virology and Cell Biology, Imperial College School of Medicine at St Mary's, Norfolk Place, London, W2 1PG, UK

    Lolita Banerji, Janet Glassford & Eric W-F Lam

  2. CRC Laboratories and Section of Cancer Cell Biology, Imperial College School of Medicine at Hammersmith Hospital, Du Cane Road, London, W12 ONN, UK

    Lolita Banerji, Janet Glassford & Eric W-F Lam

  3. Department of Haematological Medicine, Guy's, King's, St. Thomas' School of Medicine, Rayne Institute, Leukaemia Sciences, Coldharbour Lane, London, UK

    Nicholas C Lea & N Shaun B Thomas

  4. Division of Cellular Immunology, National Institute for Medical Research, Mill Hill, London, UK

    Gerry G B Klaus

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  1. Lolita Banerji
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Correspondence to Eric W-F Lam.

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Banerji, L., Glassford, J., Lea, N. et al. BCR signals target p27Kip1 and cyclin D2 via the PI3-K signalling pathway to mediate cell cycle arrest and apoptosis of WEHI 231 B cells. Oncogene 20, 7352–7367 (2001). https://doi.org/10.1038/sj.onc.1204951

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