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Activation of cyclin D1-kinase in murine fibroblasts lacking both p21Cip1 and p27Kip1

Oncogene volume 21, pages 8067–8074 (2002)Cite this article

Abstract

Deregulation of D-type cyclin-dependent kinases (CDK4 and 6) is widely observed in various human cancers, illustrating their importance in cell cycle control. Like other cyclin-dependent kinases (CDKs), assembly with cyclins is the most critical step for activation of CDK4/6. As previously reported elsewhere, we observed that the level of cyclinD1-CDK4 complex and its associated kinase activity were significantly low in asynchronously proliferating mouse embryo fibroblasts lacking both p21Cip1 and p27Kip1 (p21/p27-null MEFs). These evidences imply that p21Cip1 and p27Kip1 CDK inhibitors are ‘essential activators’ of cyclin D-kinases. We, however, discovered here that both the assembly and activation of cyclin D1-CDK4 complex occur when quiescent p21/p27-null MEFs were stimulated to re-enter the cell cycle. This mitogen-induced cyclin D1-kinase activity was blocked by overexpression of p16INK4a and resulted in the inhibition of S phase entry in p21/p27-null MEFs. Furthermore, ectopic expression of p34SEI-1, a mitogen-induced CDK4 binding protein, increased the levels of active cyclinD1-CDK4 complex in asynchronously proliferating p21/p27-null MEFs. Together, our results suggest that there are several independent ways to stimulate the assembly of cyclin D1-CDK4 kinases. Although p21Cip1 and p27Kip1 play a role in this process, our results demonstrate that additional mechanisms must occur in G0 to S phase transition.

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Acknowledgements

We greatly thank Drs CJ Sherr, JM Roberts, MF Roussel, M Cheng, JA Diehl and G Peters for providing useful materials and for reviewing the manuscript prior to submission. We are also indebted to Drs FL Graham and M Barbacid for providing us with valuable reagents. We are also grateful to Drs N Jones, N Dyson, K Helin, K Labib, DJ Mann and I Palmero for valuable suggestions. We also thank members of the Hara lab for helpful discussions during this study and the preparation of the manuscript. This work was supported by Cancer Research UK and Sumitomo Electric Industries.

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Author notes

  1. Masataka Sugimoto

    Present address: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, TN, USA

Authors and Affiliations

  1. Cancer Research UK, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, M20 4BX, UK

    Masataka Sugimoto, Nicholas Martin, Deepti P Wilks & Eiji Hara

  2. Medical & Biological Laboratories Co., Ltd., Ina, 396-0002, Nagano, Japan

    Katsuyuki Tamai

  3. Cancer Research UK, London Research Institute, London, WC2A 3PX, UK

    Thomas JG Huot

  4. Dept. of Immunology and Oncology, National Center of Biotechnology, Madrid, E-28049, Spain

    Cristina Pantoja & Manuel Serrano

  5. Dept. of Immunology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan

    Ko Okumura

  6. Dept. of Biomolecular Sciences, University of Manchester Institute of Science & Technology (UMIST), Manchester, M60 1QD, UK

    Eiji Hara

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Correspondence to Eiji Hara.

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Sugimoto, M., Martin, N., Wilks, D. et al. Activation of cyclin D1-kinase in murine fibroblasts lacking both p21Cip1 and p27Kip1. Oncogene 21, 8067–8074 (2002). https://doi.org/10.1038/sj.onc.1206019

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