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Molecular and Cellular Biology, July 2007, p. 5161-5171, Vol. 27, No. 14
0270-7306/07/$08.00+0 doi:10.1128/MCB.02431-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Cooperation between p27 and p107 during Endochondral Ossification Suggests a Genetic Pathway Controlled by p27 and p130
Nancy Yeh,1,
Jeffrey P. Miller,1,2,
Tripti Gaur,3,
Terence D. Capellini,2,
Janko Nikolich-Zugich,4
Carmen de la Hoz,1,
Licia Selleri,2
Timothy G. Bromage,5
Andre J. van Wijnen,3
Gary S. Stein,3
Jane B. Lian,3
Anxo Vidal,1* and
Andrew Koff1,2*
Laboratory of Cell Cycle Regulation, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021,1 Program in Molecular Biology, Cornell University Weill Medical School, New York, New York 10021,2 Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655,3 Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon 97006,4 Hard Tissue Research Unit, Departments of Biomaterials and Basic Sciences, New York University College of Dentistry, New York, New York 100105
Received 29 December 2006/ Returned for modification 21 February 2007/ Accepted 2 May 2007
Pocket proteins and cyclin-dependent kinase (CDK) inhibitors negatively regulate cell proliferation and can promote differentiation. However, which members of these gene families, which cell type they interact in, and what they do to promote differentiation in that cell type during mouse development are largely unknown. To identify the cell types in which p107 and p27 interact, we generated compound mutant mice. These mice were null for p107 and had a deletion in p27 that prevented its binding to cyclin-CDK complexes. Although a fraction of these animals survived into adulthood and looked similar to single p27 mutant mice, a larger number of animals died at birth or within a few weeks thereafter. These animals displayed defects in chondrocyte maturation and endochondral bone formation. Proliferation of chondrocytes was increased, and ectopic ossification was observed. Uncommitted mouse embryo fibroblasts could be induced into the chondrocytic lineage ex vivo, but these cells failed to mature normally. These results demonstrate that p27 carries out overlapping functions with p107 in controlling cell cycle exit during chondrocyte maturation. The phenotypic similarities between p107–/– p27D51/D51 and p107–/– p130–/– mice and the cells derived from them suggest that p27 and p130 act in an analogous pathway during chondrocyte maturation.
* Corresponding author. Mailing address for Andrew Koff: RRL917C, Box 207, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-2354. Fax: (646) 422-2062. E-mail: a-koff{at}ski.mskcc.org. Present address for Anxo Vidal: Department of Physiology, School of Medicine, University of Santiago de Compostela, S. Fancisco 1, 15782 Santiago de Compostela, Spain. Phone: 34-981-582658, ext. 12290. Fax: 34-981-574145. E-mail: fsavidal{at}usc.es
Published ahead of print on 14 May 2007.
N.Y. and J.P.M. contributed equally to the manuscript.
T.G. and T.D.C. contributed equally to the manuscript.
Present address: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, E-48949 Leioa, Vizcaya, Spain.
Molecular and Cellular Biology, July 2007, p. 5161-5171, Vol. 27, No. 14
0270-7306/07/$08.00+0 doi:10.1128/MCB.02431-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
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