Abstract
Cell cycle stimulation is a major transforming mechanism of Myc oncoprotein. This is achieved through at least three concomitant mechanisms: upregulation of cyclins and Cdks, downregulation of the Cdk inhibitors p15 and p21 and the degradation of p27. The Myc-p27 antagonism has been shown to be relevant in human cancer. To be degraded, p27 must be phosphorylated at Thr-187 to be recognized by Skp2, a component of the ubiquitination complex. We previously described that Myc induces Skp2 expression. Here we show that not only Cdk2 but Cdk1 phosphorylates p27 at the Thr-187. Moreover, Myc induced p27 degradation in murine fibroblasts through Cdk1 activation, which was achieved by Myc-dependent cyclin A and B induction. In the absence of Cdk2, p27 phosphorylation at Thr-187 was mainly carried out by cyclin A2-Cdk1 and cyclin B1-Cdk1. We also show that Cdk1 inhibition was enough for the synthetic lethal interaction with Myc. This result is relevant because Cdk1 is the only Cdk strictly required for cell cycle and the reported synthetic lethal interaction between Cdk1 and Myc.
Highlights
Cell cycle stimulation is a major transforming mechanism of Myc oncoprotein
The ability of Myc to overcome the p27-mediated proliferative arrest has been demonstrated in cell culture[18,19], and in animal carcinogenesis models[20]. This antagonistic effect of Myc on p27 is mediated through several concomitant mechanisms: (i) Myc induces cyclin D2 and cyclin-dependent protein kinase (Cdk)[4], which sequester p27 allowing cyclin E-Cdk[2] activation[21,22]; (ii) Myc induces expression of Cullin 1 (Cul1)[23] and Cks[124], both components of the SCFSKP2 complex and (iii) we showed that Skp[2], the p27-recognizing subunit of the SCFSKP2 ubiquitin ligase complex is a Myc target gene[25]
We first confirmed that concomitant induction of p27 and Myc-ER activation resulted in decreased p27 levels, as expected (Fig. 1a). p27 induction decreased cyclin A2 expression and this was counteracted by concomitant activation of Myc-ER, consistently with the proliferation arrest exerted by p27 and its partial rescue by Myc
Summary
Cell cycle stimulation is a major transforming mechanism of Myc oncoprotein. This is achieved through at least three concomitant mechanisms: upregulation of cyclins and Cdks, downregulation of the Cdk inhibitors p15 and p21 and the degradation of p27. At least three major mechanisms account for this: (i) the transcriptional activation of genes required for cell cycle progression, including a number of cyclins (D2, A, E);. The ability of Myc to overcome the p27-mediated proliferative arrest has been demonstrated in cell culture[18,19], and in animal carcinogenesis models[20] This antagonistic effect of Myc on p27 is mediated through several concomitant mechanisms: (i) Myc induces cyclin D2 and Cdk[4], which sequester p27 allowing cyclin E-Cdk[2] activation[21,22]; (ii) Myc induces expression of Cullin 1 (Cul1)[23] and Cks[124], both components of the SCFSKP2 complex and (iii) we showed that Skp[2], the p27-recognizing subunit of the SCFSKP2 ubiquitin ligase complex is a Myc target gene[25]. Skp[2] has been considered to have oncogenic potential and is found overexpressed in many human tumors[26,27]
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