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Post-translational modification of cyclin A1 is associated with staurosporine and TNFα induced apoptosis in leukemic cells

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Abstract

Understanding of molecular mechanisms underlying the effects of cell cycle proteins in response to the chemotherapeutic agents is of great importance for improving the efficacy of targeted therapeutics and overcoming resistance to chemotherapeutic agents. Staurosporine and tumor necrosis factor alpha (TNFα) are the therapeutic agents that inhibit tumor cell growth by inducing cell death. Staurosporine induces apoptosis through the intrinsic pathway, while TNFα trigger the cell death via the extrinsic apoptotic pathway. We have previously demonstrated that the cell cycle regulatory protein, cyclin A1 played an important role in the development of acute myeloid leukemia (AML), and cyclin A1 expression correlated with disease characteristics and patient outcome in leukemia. However, it remains unknown how cyclin A1 expression is regulated in leukemic cells treated with the therapeutic agents. Here, we demonstrate that cyclin A1 protein is regulated by proteasome-mediated ubiquitination and degradation in untreated U-937 cells. Interestingly, ubiquitination- and proteasomal-mediated degradation of cyclin A1 is prevented in cells treated with staurosporine or TNFα. Induction of apoptosis in U-937 cells by staurosporine or TNFα resulted in an increase in cyclin A1 protein expression, which correlated well with cyclin A1 protein modification and the activation of caspase-3. Blocking caspases activity by Z-VAD-FMK had no effect on the increased cyclin A1 expression, suggesting that cyclin A1 might be regulated by caspase-3 independent pathways. We further propose that CDC25C may be associated with cyclin A1 protein modification in response to staurosporine or TNFα treatment. Our results suggest that cyclin A1 protein is stabilized via post-transcriptional modification in response to apoptosis induced by staurosporine or TNFα.

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Abbreviations

TNFα:

Tumor necrosis factor alpha

AML:

Acute myeloid leukemia

ALL:

Lymphoblastic leukemia

ATRA:

All-trans retinoic acid

CHX:

Cycloheximide

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Acknowledgments

This work was supported by the Swedish National Research Council, the Swedish Cancer Society, the Swedish Children Cancer Foundation, MAS Cancer Foundation, Kunglig Fysiografisk Sällskapet in Lund, Crafoordska stiftelsen, and MAS Foundation, Gunnar Nilsson Cancer Foundation, the Government Public Health Grant (ALF), and the Medical Faculty in Lund University. We thank Cecilia Brunhoff, Elise Nilsson, and Temesgen Fufa for their technical assistance and Dr. Debra Wolgemuth for valuable suggestions.

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  1. Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, 205 02, Malmo, Sweden

    Jenny Ekberg & Jenny Liao Persson

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  1. Jenny Ekberg
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Correspondence to Jenny Liao Persson.

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Ekberg, J., Persson, J.L. Post-translational modification of cyclin A1 is associated with staurosporine and TNFα induced apoptosis in leukemic cells. Mol Cell Biochem 320, 115–124 (2009). https://doi.org/10.1007/s11010-008-9913-3

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