These findings show that, similar to Eg5, Kif15 can drive centrosome separation during bipolar spindle assembly. For this activity, Kif15 requires both its motor domain and its interaction with TPX2. Based on these data, we propose that a complex of Kif15 and TPX2 can crosslink and slide two antiparallel microtubules apart, thereby driving centrosome separation.

Inhibiting the cell-cycle kinases CDK4 and CDK6 results in significant therapeutic effect in patients with advanced hormone-positive breast cancer. The efficacy of this strategy is, however, limited by innate or acquired resistance mechanisms and its application to other tumor types is still uncertain. Here, through an integrative analysis of sensitivity and resistance mechanisms, we discuss the use of CDK4/6 inhibitors in combination with available targeted therapies, immunotherapy, or classical chemotherapy with the aim of improving future therapeutic uses of CDK4/6 inhibition in a variety of cancers. Figure 1. A Simplified View of CDK4/6 Function in Cell ProliferationCDK4 and CDK6 are activated by D-type cyclins in response to mitogenic signals. When active, these complexes phosphorylate pocket proteins of the RB1 family releasing their repressive effect on genes required for the cell cycle, such as E2F downstream targets (CCNE1, CDC6, TK1, and many others). Induction of E-type cyclins leads to the activation of downstream kinases, such as CDK2 and CDK1, which may further inactivate RB1 thereby inducing DNA replication (S phase) and chromosome segregation (mitosis). Additional CDK4/6 substrates include the FOXM1 transcription factor (which induces the expression of PLK1 and CCNB1 among other cell-cycle genes), proteins involved in the TP53 signaling pathway (MEP50), glycolytic enzymes (PFK1 and PKM2), and the ubiquitin ligase subunit SPOP involved in PDL1 degradation. Other CDK4/6-dependent phosphorylations (e.g., SMAD3, FOX03, TRIP6, NFAT) whose relevance in cancer is not clear are not shown for clarity (see Hydbring et al., 2016;Tigan et al., 2016; Wang et al., 2017 for details). In response to antimitogenic signals, monomeric CDK4 or CDK6 can be inhibited by the CDKN2 (INK4) family of proteins, including p16 INK4A (CDKN2A), p15 INK4B (CDKN2B), p18 INK4C (CDKN2C), and p19 INK4D (CDKN2D). Already-formed cyclin D-CDK4/6 complexes can be inhibited or activated by members of the CDKN1 (CIP/KIP) family composed of p21 CIP1 (CDKN1A, a TP53 transcriptional target), p27 KIP1 (CDKN1B), and p57 KIP2 (CDKN1C).

Significance Nuclear envelope breakdown (NEB) leads to the exposure of nuclear structures to cytoplasmic activities. Greatwall is a kinase able to inhibit PP2A phosphatases that counteract Cdk-dependent phosphorylation required for mitosis. Here we show that Greatwall, an essential protein in mammals, is exported to the cytoplasm in a Cdk-dependent manner before NEB, thus protecting mitotic phosphates from phosphatase activity.

Cellular senescence is a program of irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress. The underlying signalling pathways, of major clinicopathological relevance, are unknown. We combined genome-wide expression profiling with genetic complementation to identify genes that are differentially expressed when conditionally immortalised human fibroblasts undergo senescence upon activation of the p16-pRB and p53-p21 tumour suppressor pathways. This identified 816 up- and 961 down-regulated genes whose expression was reversed when senescence was bypassed. Overlay of this data set with the meta-signatures of genes up-regulated in cancer showed that nearly 50% of them were down-regulated upon senescence showing that even though overcoming senescence may only be one of the events required for malignant transformation, nearly half of the genes upregulated in cancer are related to it. Moreover 65 of the up- and 26 of the down-regulated genes are known downstream targets of NF-κB suggesting that senescence was associated with activation of the NF-κB pathway. Direct perturbation of this pathway bypasses growth arrest indicating that activation of NF-κB signalling has a causal role in promoting senescence.