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Functional analysis of cyclin D2 and p27Kip1 in cyclin D2 transgenic mouse mammary gland during development

Oncogene volume 21, pages 7214–7225 (2002)Cite this article

Abstract

Two mammary gland phenotypes were detected in pregnant MMTV-cyclin D2 transgenic mice; line D2–53 exhibited a lack of alveologenesis and failure to nurse, whereas line D2–58 featured a reduction in alveologenesis, but retained normal nursing behavior. In pregnant mammary glands, cyclin D2 protein levels were twofold (P<0.107) and 3.8-fold (P<0.0076) higher in line D2–58 and D2–53, respectively, compared to wild type. Concomitantly with the increase in cyclin D2 was a fivefold decrease in cyclin D1 hyper-phosphorylated isoform in mammary glands of pregnant cyclin D2–58 mice. Because cyclin D1 is a critical molecule in normal mammary lobuloalveolar development, these data suggest that overexpression of cyclin D2 may block mammary lobuloalveolar development through inhibition of cyclin D1 phosphorylation. During mammary gland development, p27kip1 protein level oscillated in a similar profile in wild type and cyclin D2 transgenic mice, but was consistently higher in the cyclin D2 mice suggesting that p27kip1 functions downstream of cyclin D2. The ratio of p27kip1-cdk4/p27kip1-cdk2 was 6.5-fold (P<0.0003) higher in cyclin D2 mammary glands compared to wild type in pregnant animals. This ratio reversed to 2.2-fold (P<0.005) higher in wild type compared to cyclin D2 mammary glands in involution suggesting that overexpression of cyclin D2 moderately induced apoptosis during pregnancy but accelerated involution. Collectively, the effects of cyclin D2 overexpression on mammary gland development during pregnancy and involution are attributed to two major factors, altered p27kip1 protein level and inhibition of cyclin D1 phosphorylation.

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Acknowledgements

We acknowledge Dr Charles J Sherr at the Department of Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA for the cyclin D2 cDNA. This study was supported by NIH grant CA-11944.

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  1. Gu Kong, Steven S Chua and Yi Yijun: Gu Kong and Steven S Chua participated equally in this study

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, Texas, TX, USA

    Steven S Chua, Yi Yijun, Frances Kittrell, Ricardo C Moraes, Daniel Medina & Thenaa K Said

  2. Breast Center, Baylor College of Medicine, Houston, 77030, Texas, TX, USA

    Gu Kong

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  1. Gu Kong
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Correspondence to Thenaa K Said.

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Kong, G., Chua, S., Yijun, Y. et al. Functional analysis of cyclin D2 and p27Kip1 in cyclin D2 transgenic mouse mammary gland during development. Oncogene 21, 7214–7225 (2002). https://doi.org/10.1038/sj.onc.1205895

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