Myc Stimulates Cell Cycle Progression Through the Activation of Cdk1 and Phosphorylation of p27

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.The work was supported by grant SAF2017-88026-R from MINECO, Spanish Government, to JL and MDD (partially funded by FEDER program from European Union). L.G.G. was recipient of FPI fellowship from Spanish Government. We are grateful Sandra Zunzunegui for technical assistance and John Sedivy and M. Dolores Delgado for helpful discussion

The exemplar interleaving effect in inductive learning: moderation by the difficulty of category discriminations

Recent research demonstrates a spacing effect in inductive learning. Spacing different individual exemplars apart in time, rather than massing them together, aids in the learning of categories. Experiment 1 examined whether it is interleaving or temporal spacing that is critical to the spacing effect in the situation wherethe memory load is high, and the results favored interleaving. Experiment 2 examined the effect of the difficulty of the category discrimination on presentation style (massed vs. spaced) in inductive learning, and the results demonstrated that spacing (i.e., interleaving of exemplars from different categories) is advantageous for low-discriminabilty categories, whereas massing is more effective for high-discriminability categories. In contrast to these performance measures, massing was judged by participants to be more effective than spacing in both discriminability conditions, even when performance for low-discriminability categories showed the opposite