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Constitutive cytoplasmic localization of p21Waf1/Cip1 affects the apoptotic process in monocytic leukaemia

Leukemia volume 17, pages 2113–2121 (2003)Cite this article

Abstract

In the present study, we analysed the expression and localization of p21Waf1/Cip1 in normal and malignant haematopoietic cells. We demonstrate that in normal monocytic cells, protein kinase C (PKC)-induced p21 gene activation, which is nuclear factor-κB (NF-κB) independent, results in predominantly cytoplasmic localized p21 protein. In acute monocytic leukaemia (M4, M5), monocytic blasts (N=12) show constitutive cytoplasmic p21 expression in 75% of the cases, while in myeloid leukaemic blasts (N=10), low nuclear and cytoplasmic localization of p21 could be detected, which is also PKC dependent. Constitutive p21 expression in monocytic leukaemia might have important antiapoptotic functions. This is supported by the finding that in U937 cells overexpressing p21, VP16-induced apoptosis is significantly reduced (20.0±0.9 vs 55.8±3.8%, P<0.01, N=5), reflected by a reduced phosphorylation of p38 and JNK. Similarly, AML blasts with high cytoplasmic p21 were less sensitive to VP16-induced apoptosis as compared to AML cases with low or undetectable p21 expression (42.25 vs 12.3%, P<0.01). Moreover, complex formation between p21 and ASK1 could be demonstrated in AML cells, by means of coimmunoprecipitation. In summary, these results indicate that p21 has an antiapoptotic role in monocytic leukaemia, and that p21 expression is regulated in a PKC-dependent and NF-κB-independent manner.

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Acknowledgements

We would like to thank Dr Minoru Asada from the Department of Biochemistry, The Cancer Institute, Tokyo, for the kind gift of the U937 cell lines, stable transfected with either mock- or a ZnCl2-inducible p21 construct. This study was supported by grants from the Dutch Cancer Foundation (RuG 1999-1994, RuG 2000-2316).

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  1. H Schepers and M Geugien: These two authors contributed equally to this work

Authors and Affiliations

  1. Department of Medicine, Division of Hematology, University Hospital Groningen, The Netherlands

    H Schepers, M Geugien & E Vellenga

  2. Department of Developmental Genetics, University of Groningen, The Netherlands

    H Schepers & B J L Eggen

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  1. H Schepers
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Schepers, H., Geugien, M., Eggen, B. et al. Constitutive cytoplasmic localization of p21Waf1/Cip1 affects the apoptotic process in monocytic leukaemia. Leukemia 17, 2113–2121 (2003). https://doi.org/10.1038/sj.leu.2403106

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