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Antiproliferative function of p27kip1 is frequently inhibited in highly malignant Burkitt's lymphoma cells

Oncogene volume 18, pages 6388–6397 (1999)Cite this article

Abstract

Lack of detectable expression of p27kip1 cyclin dependent kinase inhibitor has previously been correlated with high degree of malignancy in human breast, colorectal, gastric and small cell lung carcinomas. Here we demonstrate that an inverse correlation between p27kip1 expression and tumour malignancy also exists in most types of human B cell lymphomas examined. A clear exception was Burkitt's lymphoma (BL), a highly malignant tumour which often expresses high levels of p27kip1. Analysis of p27kip1 derived from Burkitt's lymphoma cell lines expressing high levels of p27kip1, BL40 and BL41, in a cyclin E/cdk2 kinase inhibition assay demonstrated that p27kip1 is not permanently inactivated since heat treatment can restore the inhibitory activity of p27kip1. However, p27kip1 expressed in these two cell lines is largely sequestered in inactive complexes and we have no evidence that c-myc or Epstein-Barr virus are responsible for the sequestration of p27kip1 in these two cell lines although c-myc and EBV are two oncogenic agents often associated with Burkitt's lymphomas. Interestingly, we observed that high level p27kip1 expression often correlated with cyclin D3 overexpression both in vivo and in BL cell lines. The majority of p27kip1 in BL40 cells was complexed with cyclin D3 indicating that overexpressed cyclin D3 may at least be part of the sequestering activity for the inhibitory function of p27kip1. Furthermore, cyclinD3/cdk4 complex could sequester p27kip1 in a cyclin E/cdk2 kinase assay in vitro. Finally, we show that cyclin D3 transfected into an inducible p27kip1 cell line could overcome the G1 arrest mediated by p27kip1. These results argue that in addition to down-regulation of p27kip1 expression, some tumour cells can sequester and tolerate the antiproliferative function of p27kip1. They also suggest a novel role for the overexpression of D-type cyclins as one pathway allowing tumour cells to overcome the antiproliferative function of p27kip1.

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Acknowledgements

We would like to thank Dr Gordon Peters for the rabbit polyclonal antibody for cyclin D1 and Dr Graham Packham for useful discussion. This work was supported by the Ludwig Institute for Cancer Research and Leukaemia Research Fund.

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Authors and Affiliations

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

    Karin Barnouin, Steffen Fredersdorf, Ayad Eddaoudi & Xin Lu

  2. Department of Histopathology, University College London Medical School, University Street, London, WC1E 6JJ, UK

    Lang Xing Pan & Ming Qin Du

  3. Institute for Cancer Research, Chester Beatty Fulham Road, London, SW3 6JB, UK

    Sibylle Mittnacht

  4. Department of Medical Microbiology, Virology and Cell Biology, Imperial College School of Medicine at St. Mary's, Norfolk Place, London, W2 1PG, UK

    Xin Lu

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  1. Karin Barnouin
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Barnouin, K., Fredersdorf, S., Eddaoudi, A. et al. Antiproliferative function of p27kip1 is frequently inhibited in highly malignant Burkitt's lymphoma cells. Oncogene 18, 6388–6397 (1999). https://doi.org/10.1038/sj.onc.1203162

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