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p16INK4a can initiate an autonomous senescence program

Oncogene volume 19, pages 1613–1622 (2000)Cite this article

Abstract

The tumor suppressor p16INK4a is a potent mediator of cell cycle arrest in transient expression studies, is induced in senescing cells, and can impose morphological features of senescence. Nonetheless, it is unclear whether p16INK4a can block cell proliferation irreversibly. We explored this issue using osteogenic sarcoma cell clones with inducible p16INK4a expression. Induction of p16INK4a for 1 day arrested most cells in G1 phase. If the induction was then interrupted, p16INK4a levels returned to baseline and robust growth resumed within 3–5 days. When p16INK4a was induced for 6 days DNA synthesis remained strongly inhibited and the cells acquired morphological features of senescence. Moreover, if p16INK4a induction was interrupted at this point and the cells were followed for 12 more days, most cells retained these morphologic features and either failed to divide or died. This occurred despite the prompt return of p16INK4a expression and retinoblastoma protein phosphorylation toward baseline levels. In fact, some senescing cells appeared to enter S phase. These results demonstrate that a sustained period of p16INK4a expression is sufficient in this setting to impose a durable block to cell proliferation and that this state becomes independent of p16INK4a expression, hypophosphorylation of pRB, or a strict G1 arrest.

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Acknowledgements

CY Dai was supported in part by National Research Service Award # 5-T32-GM 07229, for graduate studies in cell and molecular biology. This work was also supported in part by the following grants to GH Enders: a Clinical Investigator Award (7-K08-CA61412) from the National Cancer Institute, a Pilot Project grant from the University of Pennsylvania Comprehensive Cancer Center, an American Cancer Society Institutional Research Grant administered through this Center, and a Research Program Grant (#RPG-99-168-01-CCG) from the American Cancer Society. We also would like to acknowledge use of facilities of the Penn Digestive Disease Center, supported by Center Grant P30 DK50306, and the Cancer Center, supported by grants from the NCI and the Markey Charitable Trust.

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Authors and Affiliations

  1. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104-6144, Pennsylvania, PA, USA

    Charlotte Y Dai & Greg H Enders

  2. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, 19104-6144, Pennsylvania, PA, USA

    Charlotte Y Dai & Greg H Enders

  3. Program in Cell and Molecular Biology, University of Pennsylvania School of Medicine, Philadelphia, 19104-6144, Pennsylvania, PA, USA

    Charlotte Y Dai & Greg H Enders

  4. Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, 19104-6144, Pennsylvania, PA, USA

    Charlotte Y Dai & Greg H Enders

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Dai, C., Enders, G. p16INK4a can initiate an autonomous senescence program. Oncogene 19, 1613–1622 (2000). https://doi.org/10.1038/sj.onc.1203438

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