Data from Skp2 Directs Myc-Mediated Suppression of p27<sup>Kip1</sup> yet Has Modest Effects on Myc-Driven Lymphomagenesis

Abstract

<div>Abstract<p>The universal cyclin-dependent kinase inhibitor p27<sup>Kip1</sup> functions as a tumor suppressor, and reduced levels of p27<sup>Kip1</sup> connote poor prognosis in several human malignancies. p27<sup>Kip1</sup> levels are predominately regulated by ubiquitin-mediated turnover of the protein, which is marked for destruction by the E3 ubiquitin ligase SCF<sup>Skp2</sup> complex following its phosphorylation by the cyclin E–cyclin-dependent kinase 2 complex. Binding of phospho-p27<sup>Kip1</sup> is directed by the Skp2 F-box protein, and this is greatly augmented by its allosteric regulator Cks1. We have established that programmed expression of c-Myc in the B cells of Eμ-<i>Myc</i> transgenic mice triggers p27<sup>Kip1</sup> destruction by inducing Cks1, that this response controls Myc-driven proliferation, and that loss of <i>Cks1</i> markedly delays Myc-induced lymphomagenesis and cancels the dissemination of these tumors. Here, we report that elevated levels of Skp2 are a characteristic of Eμ-<i>Myc</i> lymphomas and of human Burkitt lymphoma that bear <i>MYC</i>/<i>Immunoglobulin</i> chromosomal translocations. As expected, Myc-mediated suppression of p27<sup>Kip1</sup> was abolished in <i>Skp2</i>-null Eμ-<i>Myc</i> B cells. However, the effect of Skp2 loss on Myc-driven proliferation and lymphomagenesis was surprisingly modest compared with the effects of Cks1 loss. Collectively, these findings suggest that Cks1 targets, in addition to p27<sup>Kip1</sup>, are critical for Myc-driven proliferation and tumorigenesis. Mol Cancer Res; 8(3); 353–62</p></div>