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Molecular and Cellular Biology, April 2009, p. 2254-2263, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01029-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Blockade of Protein Geranylgeranylation Inhibits Cdk2-Dependent p27Kip1 Phosphorylation on Thr187 and Accumulates p27Kip1 in the Nucleus: Implications for Breast Cancer Therapy{triangledown} ,§

Aslamuzzaman Kazi,1,2 Adam Carie,1 Michelle A. Blaskovich,1 Cynthia Bucher,1 Van Thai,1 Stacy Moulder,1,2 Hairuo Peng,3 Dora Carrico,3 Erin Pusateri,3 Warren J. Pledger,1,2 Norbert Berndt,1 Andrew Hamilton,3 and Saïd M. Sebti1,2*

Drug Discovery Program, Moffitt Cancer Center,1 and Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33612,2 Department of Chemistry, Yale University, New Haven, Connecticut 065113

Received 30 June 2008/ Returned for modification 3 October 2008/ Accepted 27 January 2009

We describe the design of a potent and selective peptidomimetic inhibitor of geranylgeranyltransferase I (GGTI), GGTI-2418, and its methyl ester GGTI-2417, which increases the levels of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 and induces breast tumor regression in vivo. Experiments with p27Kip1 small interfering RNA in breast cancer cells and p27Kip1 null murine embryonic fibroblasts demonstrate that the ability of GGTI-2417 to induce cell death requires p27Kip1. GGTI-2417 inhibits the Cdk2-mediated phosphorylation of p27Kip1 at Thr187 and accumulates p27Kip1 in the nucleus. In nude mouse xenografts, GGTI-2418 suppresses the growth of human breast tumors. Furthermore, in ErbB2 transgenic mice, GGTI-2418 increases p27Kip1 and induces significant regression of breast tumors. We conclude that GGTIs' antitumor activity is, at least in part, due to inhibiting Cdk2-dependent p27Kip1 phosphorylation at Thr187 and accumulating nuclear p27Kip1. Thus, GGTI treatment might improve the poor prognosis of breast cancer patients with low nuclear p27Kip1 levels.

* Corresponding author. Mailing address: Drug Discovery Program, Moffitt Cancer Center, 12902 Magnolia Drive, SRB3-DRDIS, Tampa, FL 33612. Phone: (813) 745-6734. Fax: (813) 745-6748. E-mail: said.sebti{at}moffitt.org

{triangledown} Published ahead of print on 9 February 2009.

§ Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2009, p. 2254-2263, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01029-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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