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Destabilization of cyclin D1 message plays a critical role in cell cycle exit upon mitogen withdrawal

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Abstract

Cyclin D1 is critical for entry into, continuation of, and exit from the cell division cycle. Mitogen stimulation of quiescent cells induces cyclin D1 expression in a transcription-dependent manner. In actively cycling cells, on the other hand, fluctuation of cyclin D1 protein levels through the cell cycle is post-transcriptionally regulated. Cyclin D1 is expressed at low levels during S phase to allow efficient DNA synthesis, and induced to high levels in G2 phase through Ras activity to commit the cells to continuing cell cycle progression. Once induced in G2 phase, cyclin D1 expression becomes Ras independent through the next G1 phase, where it promotes G1/S transition. When mitogenic signaling is abrogated, however, cyclin D1 fails to increase during G2 phase and the cell becomes arrested in the next G1 phase. In this way, the expression levels of cyclin D1 in G2 phase determine the fate of the next cell cycle. Despite its importance of the mechanism of cyclin D1 suppression upon mitogen withdrawal is unknown. Using both quantitative fluorescence microscopy and biochemical analyses, we have found that, upon serum deprivation, cyclin D1 mRNA is downmodulated without any decline in its rate of transcription. Furthermore, cyclin D1 mRNA half-life becomes shorter when serum is removed. These results demonstrate that cyclin D1 message destabilization plays a critical role in cyclin D1 suppression during G2 phase of serum-deprived cultures, and therefore in the withdrawal from the cell cycle.

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Acknowledgements

This work has been supported by NIH Grants: GM52271 and CA92194. We would like to thank Ke Yang for his helpful discussion, and Jeffery Nye and Jonathan Fretthold for their technical assistance.

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Authors and Affiliations

  1. The Department of Molecular Biology, NC2-150, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Yang Guo, Jyoti Harwalkar, Dennis W Stacey & Masahiro Hitomi

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  1. Yang Guo
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  2. Jyoti Harwalkar
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  3. Dennis W Stacey
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  4. Masahiro Hitomi
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Correspondence to Masahiro Hitomi.

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Guo, Y., Harwalkar, J., Stacey, D. et al. Destabilization of cyclin D1 message plays a critical role in cell cycle exit upon mitogen withdrawal. Oncogene 24, 1032–1042 (2005). https://doi.org/10.1038/sj.onc.1208299

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