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CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells

Oncogene volume 22, pages 4143–4149 (2003)Cite this article

Abstract

Cell proliferation and differentiation are highly coordinated during normal development. Many tumor cells exhibit both uncontrolled proliferation and a block to terminal differentiation. To understand the mechanisms coordinating these two processes, we have investigated the relation between cyclin-dependent kinase (CDK) activities and the block to differentiation in murine erythroleukemia (MEL) cells. We found that CDK6 (but not CDK4) is rapidly downregulated as MEL cells are induced to re-enter erythroid differentiation and that maintenance of CDK6 (but not CDK4) activity by transfection blocks differentiation. Moreover, we found that PU.1, an Ets transcription factor that is oncogenic in erythroid cells and also can block their differentiation, controls the synthesis of CDK6 mRNA. These results suggest a mechanism for coupling proliferation and the block to differentiation in these leukemic cells through the action of an oncogenic transcription factor (PU.1) on a key cell cycle regulator (CDK6). Our findings suggest that studying the relative roles of CDK6 and CDK4 in other types of malignant cells will be important in designing approaches for cell cycle inhibition and differentiation therapy in cancer.

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Acknowledgements

We are extremely grateful to David Franklin and Yue Xiong for providing us with constructs, antibodies, technical support and advice that were essential to the completion of these experiments. We also thank Richard Pestell and Liang Zhu for providing us with critical reagents and advice. AIS receives support from National Cancer Institute Cancer Center Grant 2P30CA13330, FR was supported by NIH 5T32AG00194 and IM was supported by NIH/MSTP 5T32GM07288-25. This work was supported by NIH Grant 5R37CA16368.

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  1. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, 10461, NY, USA

    Igor Matushansky, Farshid Radparvar & Arthur I Skoultchi

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  1. Igor Matushansky
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Correspondence to Arthur I Skoultchi.

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Matushansky, I., Radparvar, F. & Skoultchi, A. CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells. Oncogene 22, 4143–4149 (2003). https://doi.org/10.1038/sj.onc.1206484

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