Light and gibberellins (GAs) mediate many essential and partially overlapping plant developmental processes. DELLA proteins are GA-signalling repressors that block GA-induced development 1 . GA induces degradation of DELLA proteins via the ubiquitin/ proteasome pathway 2 , but light promotes accumulation of DELLA proteins by reducing GA levels 3 . It was proposed that DELLA proteins restrain plant growth largely through their effect on gene expression 4,5 . However, the precise mechanism of their function in coordinating GA signalling and gene expression remains unknown. Here we characterize a nuclear protein interaction cascade mediating transduction of GA signals to the activity regulation of a light-responsive transcription factor. In the absence of GA, nuclear-localized DELLA proteins accumulate to higher levels, interact with phytochrome-interacting factor 3 (PIF3, a bHLH-type transcription factor) and prevent PIF3 from binding to its target gene promoters and regulating gene expression, and therefore abrogate PIF3-mediated light control of hypocotyl elongation. In the presence of GA, GID1 proteins (GA receptors) elevate their direct interaction with DELLA proteins in the nucleus, trigger DELLA protein's ubiquitination and proteasome-mediated degradation, and thus release PIF3 from the negative effect of DELLA proteins.Light and GA interact during Arabidopsis thaliana seedling development, regulating hypocotyl elongation, cotyledon opening and light-responsive gene expression; their pathways seem to converge at regulation of the abundance of DELLA proteins (GA pathway repressors) 3,6 . Arabidopsis has five DELLA proteins-RGA, GAI, RGL1, RGL2 and RGL3-defined by their unique DELLA domain and a conserved GRAS domain 4 . To analyse them in vivo, we raised antibodies against endogenous RGA and generated transgenic Arabidopsis expressing each of the five DELLA proteins with tandem affinity purification (TAP) tags ( Supplementary Fig. 1). The response of DELLA protein levels to exogenously applied GA 3 (an active form of GA) or PAC (paclobutrazol, a GA biosynthesis inhibitor) was examined. We found that one-hour-long GA treatment eliminates the majority of DELLA proteins, and this GA effect can be largely prevented by 100 mM MG132 (a 26S proteasome-specific inhibitor). PAC, on the other hand, promotes over-accumulation of DELLA proteins (Fig. 1). These results show for the first time in Arabidopsis that all the DELLA proteins are under negative control by GA and the proteasome. Next, we generated lines expressing TAPtagged RGAD17 and GAID17, which lack a 17 amino acid motif within the DELLA domain that is required for GA-induced degradation 7,8 . As expected, TAP-RGAD17 and TAP-GAID17 are completely resistant to GA and accumulate at higher levels than wild-type proteins, which cannot be further increased by PAC (Fig. 1, and *These authors contributed equally to this work. WTAnti-RPN6Anti-RGA Immunoblot analysis of RGA (by anti-RGA antibody) and TAP-DELLA proteins (by anti-MYC antibody) in various light-grown Ara...

Echinoid is an immunoglobulin domain-containing transmembrane protein that modulates cell-cell signaling by Notch and the EGF receptors. We show that, in the Drosophila wing disc epithelium, Echinoid is a component of adherens junctions that cooperates with DE-Cadherin in cell adhesion. Echinoid and beta-catenin (a DE-Cadherin interacting protein) each possess a C-terminal PDZ domain binding motif that binds to Bazooka/PAR-3; these motifs redundantly position Bazooka to adherens junctions. Echinoid also links to actin filaments by binding to Canoe/AF-6/afadin. Moreover, interfaces between Echinoid- and Echinoid+ cells, like those between DE-Cadherin- and DE-Cadherin+ cells, are deficient in adherens junctions and form actin cables. These characteristics probably facilitate the strong sorting behavior of cells that lack either of these cell-adhesion molecules. Finally, cells lacking either Echinoid or DE-Cadherin accumulate a high density of the reciprocal protein, further suggesting that Echinoid and DE-Cadherin play similar and complementary roles in cell adhesion.

SUMMARY Homeotic (HOX) genes are dysregulated in multiple malignancies including several AML subtypes. We demonstrate that H3K79 dimethylation (H3K79me2) is converted to mono-methylation (H3K79me1) at HOX loci as hematopoietic cells mature thus coinciding with a decrease in HOX gene expression. We show that H3K79 methyltransferase activity as well as H3K79me1 to H3K79me2 conversion is regulated by the DOT1L co-factor AF10. AF10 inactivation reverses leukemia-associated epigenetic profiles, precludes abnormal HOXA gene expression and impairs the transforming ability of MLL-AF9, MLL-AF6 or NUP98-NSD1 fusions – mechanistically distinct HOX-activating oncogenes. Furthermore, NUP98-NSD1 transformed cells are sensitive to small-molecule inhibition of DOT1L. Our findings demonstrate that pharmacological inhibition of the DOT1L/AF10 complex may provide therapeutic benefit in an array of malignancies with abnormal HOXA gene expression.

The role of IL-6 was investigated in murine ischemic acute renal failure. The renal pedicles were clamped for 17 min, and the mice were studied at various times after reperfusion. We found that serum IL-6 increased after murine ischemic renal injury. This increase was associated with increased IL-6 mRNA in the ischemic kidney but not in the contralateral kidney or the liver. Maximal IL-6 production occurred at 4 to 8 h and decreased to baseline by 24 h. Reperfusion of the kidney was required for IL-6 production. In situ hybridization and immunohistochemistry showed that macrophages infiltrated areas adjacent to the vascular bundles in the outer medulla within hours of reperfusion and showed that these macrophages produced IL-6 mRNA. For understanding how macrophages were stimulated to produce IL-6, an in vitro model in which S3 proximal tubular cells were injured by reactive oxygen species was set up. These injured cells released molecules that activated macrophages to produce IL-6 in vitro. IL-6 that was produced in response to renal ischemia was maladaptive because transgenic knockout of IL-6 ameliorated renal injury as measured by serum creatinine and histology. IL-6 transgenic knockout mice were lethally irradiated, and their bone marrow was reconstituted with wild-type IL-6 cells. Such bone marrow transfers abolished the protective effects of transgenic IL-6 knockout. It is concluded that macrophages infiltrate the area of the vascular bundles of the outer medulla, these macrophages produce IL-6, and this IL-6 exacerbates ischemic murine acute renal failure.

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