The retinoblastoma tumor suppressor protein (pRB) and related p107 and p130 "pocket proteins" function together with the E2F transcription factors to repress gene expression during the cell cycle and development. Recent biochemical studies have identified the multisubunit DREAM pocket protein complexes in Drosophila melanogaster and Caenorhabditis elegans in regulating developmental gene repression. Although a conserved DREAM complex has also been identified in mammalian cells, its physiological function in vivo has not been determined. Here we addressed this question by targeting Lin9, a conserved core subunit of DREAM. We found that LIN9 is essential for early embryonic development and for viability of adult mice. Loss of Lin9 abolishes proliferation and leads to multiple defects in mitosis and cytokinesis because of its requirement for the expression of a large set of mitotic genes, such as Plk1, Aurora A, and Kif20a. While Lin9 heterozygous mice are healthy and normal, they are more susceptible to lung tumorigenesis induced by oncogenic c-Raf than wild-type mice. Together these experiments provide the first direct genetic evidence for the role of LIN9 in development and mitotic gene regulation and they suggest that it may function as a haploinsufficient tumor suppressor.The retinoblastoma tumor suppressor protein (pRB) and related p107 and p130 "pocket proteins" function together with the E2F transcription factors to regulate gene expression during the cell cycle (7). The identification of evolutionary conserved pocket protein/E2F complexes in Drosophila melanogaster has provided new insights into E2F-mediated gene regulation (21,24). These multisubunit complexes, alternatively called dREAM or Myb-MuvB (MMB), consist of at least eight subunits, including the repressor dE2F2 and one of the two retinoblastoma-related proteins, RBF1 or RBF2. In addition, the complex also contains Drosophila dMYB and three Myb-interacting proteins. RNA interference (RNAi)-mediated depletion of several subunits of the complex demonstrated a role in stable repression of developmental genes, although more recent genome-wide studies have found that dREAM/ MMB also functions in activation of genes involved in G 2 and mitosis (2,13,21,24).Remarkably, all subunits of dREAM/MMB, except for dMYB, are related to the Caenorhabditis elegans synMuv class B genes that antagonize RAS-induced vulva differentiation (3,9). Indeed, several synMuv proteins form a multisubunit complex that is highly related to dREAM/MMB (14). Therefore, in analogy to dREAM/MMB, it has been suggested that DRM mainly functions in gene repression during development (14).We and others recently identified a complex in human cells that is closely related to dREAM and DRM (20,25,31,40). The human complex, alternatively called LINC or human DREAM, consists of a five-protein core module that binds in quiescent cells to the repressors p130 and E2F4. In S phase this binding is lost and B-MYB associates with the complex. The high degree of conservation of the DREAM-like complex...

Background: p21 is induced when Aurora B is inhibited. Results: p21-induction after Aurora B inhibition is attributed to aneuploidy and reactive oxygen species. Conclusion: Aneuploidy and ROS mediate cell cycle arrest after Aurora B inhibition by promoting p21-induction. Significance: The study contributes to the understanding of the mechanisms for p21-induction and cell cycle arrest following an aberrant mitosis.

Aurora kinases play important functions in mitosis. They are overexpressed in many cancers and are targets for anticancer therapy. Inhibition of Aurora B results in cytokinesis failure and polyploidization, leading to activation of the p53 tumor suppressor and its target genes, including p21. The pathways that mediate p21 activation after Aurora B inhibition are not well understood. In this study, we identified a role for the p38 MAP kinase in activation of p21 when Aurora B is inhibited. We show that p38 is required for the acute cell cycle arrest in G 1 and to prevent endoreduplication when Aurora B is inhibited. Stabilization of p53 occurs independently of p38, and recruitment of p53 to the p21 promoter also does not require p38. Instead, enrichment of the elongating form of RNA PolII at the distal region of the p21 gene is strongly reduced when p38 is blocked, indicating that p38 acts in transcriptional elongation of p21. Thus, our results identify an unexpected role of p38 in cell cycle regulation in response to Aurora B inhibition, by promoting the transcriptional elongation of the cell cycle inhibitor p21.

The DREAM complex is an important regulator of mitotic gene expression during the cell cycle. Here we report that inactivation of LIN9, a subunit of DREAM, results in premature senescence, which can be overcome by the SV40 large T (LT) antigen. Together with the observation that p16 INK4a and p21 Waf1 are upregulated upon loss of LIN9, these results indicate that senescence is triggered by the pRB and p53 tumor suppressor pathways. We also find that LIN9-null cells that escape senescence are chromosomally instable because of compromised mitotic fidelity. SV40 LT-expressing cells that adapt to the loss of LIN9 can grow anchorage-independently in soft agar, a hallmark of oncogenic transformation. Taken together, these results suggest an important role of mitotic gene regulation in the maintenance of genomic stability and tumor suppression.

The most common interventions for children with lexical disorders are forms and combinations of interventions focusing on phonological and semantic elaboration and retrieval. Systematic reviews of intervention studies on children with lexical disorders show that a significant generalization of therapeutic effects to untrained vocabulary was rarely achieved. The aim of this study was to investigate whether preschool children with lexical deficits profit from an intervention approach that focuses on implementing lexical learning strategies. A randomized controlled trial was conducted. The control group consisted of 25 children, who received language support in their kindergarten. The 26 children in the experimental group additionally received 15 intervention sessions of the lexical strategy intervention 'lexicon pirate'. Intervention effects were measured using a standardized expressive vocabulary assessment one year after the intervention. All children significantly improved on the expressive vocabulary measure. In addition, the gain in expressive vocabulary size was higher for children in the experimental group than for the participants in the control group. Further analysis revealed that 'lexicon pirate' was as effective for children with qualitative (word-finding) lexical deficits as for those with quantitative (vocabulary) lexical deficits. The gain in expressive vocabulary size was independent of nonverbal IQ, deficits in phonological working memory or other possible influencing factors.