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Deregulated expression of cyclin D1 overrides antimitogenic signals

Oncogene volume 19, pages 315–322 (2000)Cite this article

Abstract

Several types of epithelial neoplasms exhibit high expression of transforming growth factor β1 (TGFβ-1), indicating that they have acquired tolerance to this normally growth inhibitory cytokine. Since cyclin D1 is expressed at high levels in murine skin tumors coincident with high levels of TGFβ-1 expression, we hypothesized that cyclin D1 may override TGFβ-1 induced growth arrest. We observed that in primary murine keratinocytes treated with TGFβ-1, cyclin D1 is quickly suppressed at both the mRNA and protein level. Since changes in other cell cycle proteins occur at a later time during TGFβ-1 treatment, the early suppression of cyclin D1 suggests that this gene is a critical target for TGFβ-1 growth suppression. Using primary keratinocytes from transgenic mice that overexpress cyclin D1 (K5-D1 mice), we observed partial resistance to TGFβ-1 growth inhibition. This resistance involves changes in the cyclin/cdk/inhibitor complexes rather than differences in expression of the TGFβ receptors or signaling. Comparison of cdk associated kinase activity between wild-type and K5-D1 cells shows differential regulation. We conclude that deregulated cyclin D1 and subsequent alterations in cell cycle machinery provides keratinocytes the ability to at least partially override growth inhibitory signals.

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Abbreviations

TGFβ-1:

Transforming growth factor β

cdk:

cyclin dependent kinase

pRb:

retinoblastoma protein

BrdU:

bromodeoxyurindine

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Acknowledgements

We would like to thank Melissa Bracher for helping with the preparation of this manuscript, Judy G Ing and the Art Department for the art work and Marilyn Lee for culture setups. We are very grateful to April Ott for her assistance with animal management. We also want to thank Ana Robles for help and advice during the course of this project. This work was supported in part by NIH grants CA42157 (CJ Conti), CA34443 (SM Fischer), CA16672 and NIEHS Center Grant ES07784.

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Authors and Affiliations

  1. Science Park-Research Division, The University of Texas MD Anderson Cancer Research Center, Park Road 1-C, Smithville, 78957, Texas, TX, USA

    LA Martinez, A Pavone, SM Fischer & CJ Conti

  2. Center for Molecular & Structural Biology, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Avenue, South Carolina, Charleston, 29425–2213, SC, USA

    Y Chen

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  1. LA Martinez
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  2. Y Chen
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Martinez, L., Chen, Y., Pavone, A. et al. Deregulated expression of cyclin D1 overrides antimitogenic signals. Oncogene 19, 315–322 (2000). https://doi.org/10.1038/sj.onc.1203301

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