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  • Original Paper
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Role of Gadd45α in the density-dependent G1 arrest induced by p27Kip1

Oncogene volume 22, pages 4166–4174 (2003)Cite this article

Abstract

p27Kip1, an inhibitor of cyclin-dependent kinases, is an important regulator of cell cycle progression. We have previously shown that p27Kip1 inhibits the G0 to S transition when ectopically expressed in p27-47 mouse fibroblasts arrested at high but not low densities. In the study described here, we identify Gadd45α, a member of the growth arrest- and DNA damage-inducible family of proteins, as a potential mediator of the density-dependent effects of p27Kip1 on cell proliferation. Gadd45α mRNA and protein were more abundant in p27-47 cells arrested at high densities than at low densities. Amounts of both decreased and remained low when cells arrested at high densities were exposed to mitogens in the absence, but not in the presence, of ectopically expressed p27Kip1. Importantly, enforced expression of Gadd45α prevented density-arrested mouse fibroblasts from initiating DNA synthesis in response to mitogens. We suggest that amounts of Gadd45α above a certain threshold are growth inhibitory and that such amounts are achieved in cells arrested at high but not low densities. For cultures arrested at high densities, the resumption of cell cycle traverse requires a sustained reduction in Gadd45α abundance, a process that is induced by mitogens and inhibited by p27Kip1.

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Acknowledgements

This work was supported by the Cortner-Couch Endowed Chair for Cancer Research and NIH Grant CA67360 (WJP). We thank Dr Albert Fornace for providing the Gadd45α coding sequence, Dr Nancy Olashaw for the manuscript preparation, and Dr Shrinkant Mane of the Microarray Core Facility at the Moffitt Cancer Center for his assistance in the performance and interpretation of the microarray analyses. We also acknowledge the helpful service of the Flow Cytometry and Molecular Imaging Core Laboratories at the Moffitt Cancer Center.

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Authors and Affiliations

  1. Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, 33612, FL, USA

    Xiaohong Zhang, Le Ma, Steven A Enkemann & W J Pledger

  2. Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, 33612, FL, USA

    Xiaohong Zhang, Le Ma, Steven A Enkemann & W J Pledger

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  1. Xiaohong Zhang
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Correspondence to W J Pledger.

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Zhang, X., Ma, L., Enkemann, S. et al. Role of Gadd45α in the density-dependent G1 arrest induced by p27Kip1. Oncogene 22, 4166–4174 (2003). https://doi.org/10.1038/sj.onc.1206599

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