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Molecular and Cellular Biology, August 2006, p. 6170-6184, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.02182-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

p27^Kip1 and p130 Cooperate To Regulate Hematopoietic Cell Proliferation In Vivo

Department of Oncology and Cancer Research UK Labs, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom,¹ King's College London, Department of Haematological Medicine, The Rayne Institute, 123 Coldharbour Lane, London SE5 9NU, United Kingdom,² Department of Pathology, Cancer Studies Division, Birmingham University, Birmingham B15 2TT, United Kingdom,³ Department of Histopathology, Hammersmith Hospital & Imperial College London, Du Cane Road, London W12 0HS, United Kingdom,⁴ Biochemistry Building, Division of Cell and Molecular Biology, Faculty of Life Sciences, Imperial College, South Kensington, London SW7 2AZ, United Kingdom,⁵ Department of Virology, Faculty of Medicine, St. Mary's Campus, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom⁶

Received 10 November 2005/ Returned for modification 9 December 2005/ Accepted 27 May 2006

To investigate the potential functional cooperation between p27^Kip1 and p130 in vivo, we generated mice deficient for both p27^Kip1 and p130. In p27^Kip1–/–; p130^–/– mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27^Kip1–/– counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27^Kip1–/–; p130^–/– animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27^Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27^Kip1–/– splenocytes. The finding that the p27^Kip1–/–; p130^–/– splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27^Kip1 to regulate hematopoietic cell proliferation in vivo.

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