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Molecular and Cellular Biology, March 2003, p. 1764-1774, Vol. 23, No. 5
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.5.1764-1774.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Hsc70 Regulates Accumulation of Cyclin D1 and Cyclin D1-Dependent Protein Kinase

J. Alan Diehl,1* Wensheng Yang,1 Ronald A. Rimerman,2 Hua Xiao,3 and Andrew Emili4

The Leonard and Madlyn Abramson Family Cancer Research Institute, Department of Cancer Biology, Abramson Cancer Center at the University of Pennsylvania, Philadelphia, Pennsylvania 19104,1 Department of Pharmacology,2 The Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198,3 Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada4

Received 12 July 2002/ Returned for modification 12 August 2002/ Accepted 2 December 2002

The cyclin D-dependent kinase is a critical mediator of mitogen-dependent G1 phase progression in mammalian cells. Given the high incidence of cyclin D1 overexpression in human neoplasias, the nature and complexity of cyclin D complexes in vivo have been subjects of intense interest. Besides its catalytic partner, the nature and complexity of cyclin D complexes in vivo remain ambiguous. To address this issue, we purified native cyclin D1 complexes from proliferating mouse fibroblasts by affinity chromatography and began to identify and functionally characterize the associated proteins. In this report, we describe the identification of Hsc70 and its functional importance for cyclin D1 and cyclin D1-dependent kinase maturation. We demonstrate that Hsc70 associates with newly synthesized cyclin D1 and is a component of a mature, catalytically active cyclin D1/CDK4 holoenzyme complex. Our data suggest that Hsc70 promotes stabilization of newly synthesized cyclin D1, thereby increasing its availability for assembly with CDK4. In addition, our data demonstrate that Hsc70 remains bound to cyclin D1 following its assembly with CDK4 and Cip/Kip proteins, where it ensures the formation of a catalytically active complex.

* Corresponding author. Mailing address: The Leonard and Madlyn Abramson Family Cancer Research Institute, Department of Cancer Biology, Abramson Cancer Center at UPenn, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 746-6389. Fax: (215) 746-5511. E-mail: adiehl{at}mail.med.upenn.edu.

Molecular and Cellular Biology, March 2003, p. 1764-1774, Vol. 23, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.5.1764-1774.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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