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Molecular and Cellular Biology, May 2002, p. 2993-3002, Vol. 22, No. 9
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.9.2993-3002.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Altered p27Kip1 Phosphorylation, Localization, and Function in Human Epithelial Cells Resistant to Transforming Growth Factor ß-Mediated G1 Arrest

Sandra Ciarallo, Venkateswaran Subramaniam, Wesley Hung, Jin-Hwa Lee, Rouslan Kotchetkov, Charanjit Sandhu, Andrea Milic, and Joyce M. Slingerland*

Molecular and Cell Biology, Sunnybrook & Women's College Health Sciences Centre, University of Toronto, Toronto, Canada

Received 10 January 2001/ Returned for modification 27 February 2001/ Accepted 22 January 2002

p27Kip1 is an important effector of G1 arrest by transforming growth factor ß (TGF-ß). Investigations in a human mammary epithelial cell (HMEC) model, including cells that are sensitive (184S) and resistant (184A1L5R) to G1 arrest by TGF-ß, revealed aberrant p27 regulation in the resistant cells. Cyclin E1-cyclin-dependent kinase 2 (cdk2) and cyclin A-cdk2 activities were increased, and p27-associated kinase activity was detected in 184A1L5R cells. p27 from 184A1L5R cells was localized to both nucleus and cytoplasm, showed an altered profile of phosphoisoforms, and had a reduced ability to bind and inhibit cyclin E1-cdk2 in vitro when compared to p27 from the sensitive 184S cells. In proliferating 184A1L5R cells, more p27 was associated with cyclin D1-cdk4 complexes than in 184S. While TGF-ß inhibited the formation of cyclin D1-cdk4-p27 complexes in 184S cells, it did not inhibit the assembly of cyclin D1-cdk4-p27 complexes in the resistant 184A1L5R cells. p27 phosphorylation changed during cell cycle progression, with cyclin E1-bound p27 in G0 showing a different phosphorylation pattern from that of cyclin D1-bound p27 in mid-G1. These data suggest a model in which TGF-ß modulates p27 phosphorylation from its cyclin D1-bound assembly phosphoform to an alternate form that binds tightly to inhibit cyclin E1-cdk2. Altered phosphorylation of p27 in the resistant 184A1L5R cells may favor the binding of p27 to cyclin D1-cdk4 and prevent its accumulation in cyclin E1-cdk2 in response to TGF-ß.

* Corresponding author. Mailing address: Molecular and Cell Biology, Sunnybrook & Women's College Health Sciences Centre, 2075 Bayview Ave., Toronto, Ontario, Canada M4N 3M5. Phone: (416) 480-6100, ext. 3494. Fax: (416) 480-5703. E-mail: joyce.slingerland{at}utoronto.ca.

Molecular and Cellular Biology, May 2002, p. 2993-3002, Vol. 22, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.9.2993-3002.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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