Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27 Kip1 phosphorylation on Thr187 and accumulates p27 Kip1 in the nucleus: Implications for breast cancer therapy

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

Research output: Contribution to journalArticle

Abstract

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 p27 Kip1 and induces breast tumor regression in vivo. Experiments with p27 Kip1 small interfering RNA in breast cancer cells and p27 Kip1 null murine embryonic fibroblasts demonstrate that the ability of GGTI-2417 to induce cell death requires p27 Kip1. GGTI-2417 inhibits the Cdk2-mediated phosphorylation of p27 Kip1 at Thr187 and accumulates p27 Kip1 in the nucleus. In nude mouse xenografts, GGTI-2418 suppresses the growth of human breast tumors. Furthermore, in ErbB2 transgenic mice, GGTI-2418 increases p27 Kip1 and induces significant regression of breast tumors. We conclude that GGTIs' antitumor activity is, at least in part, due to inhibiting Cdk2-dependent p27 Kip1 phosphorylation at Thr187 and accumulating nuclear p27 Kip1. Thus, GGTI treatment might improve the poor prognosis of breast cancer patients with low nuclear P27 Kip1 levels.

Original languageEnglish (US)
Pages (from-to)2254-2263
Number of pages10
JournalMolecular and cellular biology
Volume29
Issue number8
DOIs
StatePublished - Apr 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Kazi, A., Carie, A., Blaskovich, M. A., Bucher, C., Thai, V., Moulder, S., Peng, H., Carrico, D., Pusateri, E., Warren, J. P., Berndt, N., Hamilton, A., & Sebti, S. M. (2009). Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27 Kip1 phosphorylation on Thr187 and accumulates p27 Kip1 in the nucleus: Implications for breast cancer therapy. Molecular and cellular biology, 29(8), 2254-2263. https://doi.org/10.1128/MCB.01029-08