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Molecular and Cellular Biology, September 2001, p. 6254-6269, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6254-6269.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Tumor-Specific Proteolytic Processing of Cyclin E Generates Hyperactive Lower-Molecular-Weight Forms

Donald C. Porter,1 Ning Zhang,2 Christopher Danes,1 Mollianne J. McGahren,2 Richard M. Harwell,1,3 Shamsa Faruki,1 and Khandan Keyomarsi1,2,3,*

Division of Molecular Medicine, Wadsworth Center, Albany, New York 12201-05091; Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 770302; and Department of Biomedical Sciences, State University of New York, Albany, New York 122223

Received 16 March 2001/Returned for modification 11 May 2001/Accepted 18 June 2001

Cyclin E is a G1 cyclin essential for S-phase entry and has a profound role in oncogenesis. Previously this laboratory found that cyclin E is overexpressed and present in lower-molecular-weight (LMW) isoforms in breast cancer cells and tumor tissues compared to normal cells and tissues. Such alteration of cyclin E is linked to poor patient outcome. Here we report that the LMW forms of cyclin E are hyperactive biochemically and they can more readily induce G1-to-S progression in transfected normal cells than the full-length form of the protein can. Through biochemical and mutational analyses we have identified two proteolytically sensitive sites in the amino terminus of human cyclin E that are cleaved to generate the LMW isoforms found in tumor cells. Not only are the LMW forms of cyclin E functional, as they phosphorylate substrates such as histone H1 and GST-Rb, but also their activities are higher than the full-length cyclin E. These nuclear localized LMW forms of cyclin E are also biologically functional, as their overexpression in normal cells increases the ability of these cells to enter S and G2/M. Lastly, we show that cyclin E is selectively cleaved in vitro by the elastase class of serine proteases to generate LMW forms similar to those observed in tumor cells. These studies suggest that the defective entry into and exit from S phase by tumor cells is in part due to the proteolytic processing of cyclin E, which generates hyperactive LMW isoforms whose activities have been modified from that of the full-length protein.

* Corresponding author. Mailing address: Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 66, Houston, TX 77030-4095. Phone: (713) 792-4845. Fax: (713) 794-5369. E-mail: kkeyomar{at}mdanderson.org.

Molecular and Cellular Biology, September 2001, p. 6254-6269, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6254-6269.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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