Phosphoinositides are a family of lipid signalling molecules that regulate many cellular functions in eukaryotes. Phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2), the central component in the phosphoinositide signalling circuitry, is generated primarily by type I phosphatidylinositol 4-phosphate 5-kinases (PIPKIalpha, PIPKIbeta and PIPKIgamma). In addition to functions in the cytosol, phosphoinositides are present in the nucleus, where they modulate several functions; however, the mechanism by which they directly regulate nuclear functions remains unknown. PIPKIs regulate cellular functions through interactions with protein partners, often PtdIns4,5P2 effectors, that target PIPKIs to discrete subcellular compartments, resulting in the spatial and temporal generation of PtdIns4,5P2 required for the regulation of specific signalling pathways. Therefore, to determine roles for nuclear PtdIns4,5P2 we set out to identify proteins that interacted with the nuclear PIPK, PIPKIalpha. Here we show that PIPKIalpha co-localizes at nuclear speckles and interacts with a newly identified non-canonical poly(A) polymerase, which we have termed Star-PAP (nuclear speckle targeted PIPKIalpha regulated-poly(A) polymerase) and that the activity of Star-PAP can be specifically regulated by PtdIns4,5P2. Star-PAP and PIPKIalpha function together in a complex to control the expression of select mRNAs, including the transcript encoding the key cytoprotective enzyme haem oxygenase-1 (refs 8, 9) and other oxidative stress response genes by regulating the 3'-end formation of their mRNAs. Taken together, the data demonstrate a model by which phosphoinositide signalling works in tandem with complement pathways to regulate the activity of Star-PAP and the subsequent biosynthesis of its target mRNA. The results reveal a mechanism for the integration of nuclear phosphoinositide signals and a method for regulating gene expression.
Phosphoinositide-specific phospholipase C (PI-PLC) plays a pivotal role in regulation of intracellular signal transduction from various receptor molecules. More than 10 members of human PI-PLC isoforms have been identified and classified into three classes , ␥, and ␦, which are regulated by distinct mechanisms. Here we report identification of a novel class of human PI-PLC, named PLC⑀, which is characterized by the presence of a Ras-associating domain at its C terminus and a CDC25-like domain at its N terminus. The Ras-associating domain of PLC⑀ specifically binds to the GTP-bound forms of Ha-Ras and Rap1A. The dissociation constant for HaRas is estimated to be approximately 40 nM, comparable with those of other Ras effectors. Co-expression of an activated Ha-Ras mutant with PLC⑀ induces its translocation from the cytosol to the plasma membrane. Upon stimulation with epidermal growth factor, similar translocation of ectopically expressed PLC⑀ is observed, which is inhibited by co-expression of dominant-negative Ha-Ras. Furthermore, using a liposome-based reconstitution assay, it is shown that the phosphatidylinositol 4,5-bisphosphate-hydrolyzing activity of PLC⑀ is stimulated in vitro by Ha-Ras in a GTP-dependent manner. These results indicate that Ras directly regulates phosphoinositide breakdown through membrane targeting of PLC⑀.
Background-J Wave Syndromes have emerged conceptually to encompass the pleiotropic expression of J point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). Recently, KCNJ8, which encodes the cardiac K ATP Kir6.1 channel, has been implicated in ERS following the identification of a functionally uncharacterized missense mutation, S422L. Here, we sought to further explore KCNJ8 as a novel susceptibility gene for J wave syndromes.
• Ikaros controls cellular proliferation by repressing genes that regulate cell cycle progression and the PI3K pathway in leukemia.• CK2 inhibitor restores Ikaros tumor suppressor function in high-risk B-ALL with IKZF1 deletion and has a strong therapeutic effect in vivo.Ikaros (IKZF1) is a tumor suppressor that binds DNA and regulates expression of its target genes. The mechanism of Ikaros activity as a tumor suppressor and the regulation of Ikaros function in leukemia are unknown. Here, we demonstrate that Ikaros controls cellular proliferation by repressing expression of genes that promote cell cycle progression and the phosphatidylinositol-3 kinase (PI3K) pathway. We show that Ikaros function is impaired by the pro-oncogenic casein kinase II (CK2), and that CK2 is overexpressed in leukemia. CK2 inhibition restores Ikaros function as transcriptional repressor of cell cycle and PI3K pathway genes, resulting in an antileukemia effect. In high-risk leukemia where one IKZF1 allele has been deleted, CK2 inhibition restores the transcriptional repressor function of the remaining wild-type IKZF1 allele. CK2 inhibition demonstrated a potent therapeutic effect in a panel of patient-derived primary high-risk B-cell acute lymphoblastic leukemia xenografts as indicated by prolonged survival and a reduction of leukemia burden. We demonstrate the efficacy of a novel therapeutic approach for high-risk leukemia: restoration of Ikaros tumor suppressor activity via inhibition of CK2. These results provide a rationale for the use of CK2 inhibitors in clinical trials for high-risk leukemia, including cases with deletion of one IKZF1 allele. (Blood. 2015;126(15):1813-1822 Introduction Ikaros (IKZF1) activity is essential for normal hematopoiesis and immune development. [1][2][3][4] Ikaros knockout mice have severely impaired hematopoiesis, 5-7 whereas mice with the heterozygous loss of Ikaros develop T-cell leukemia. 8 In humans, impaired Ikaros activity due to the deletion or inactivating mutation of a single IKZF1 allele results in high-risk B-cell leukemia that is resistant to treatment.9-14 Ikaros regulates transcription of target genes via chromatin remodeling. [15][16][17] Ikaros activity is controlled through multiple mechanisms. Mouse studies suggest that the transcription of IKZF1 during normal hematopoiesis is regulated by a complex network. 18 However, Ikaros protein is expressed at high levels in most hematopoietic cells, and posttranslational modifications are hypothesized to play a critical role in regulating Ikaros activity. 19 Several groups have shown that phosphorylation, [19][20][21][22][23][24] sumoylation, 25 and ubiquitination 22 can regulate Ikaros function as a transcriptional repressor. However, the role of posttranslational modification in the regulation of Ikaros tumor suppressor activity in leukemia is unknown.Despite extensive global analyses of Ikaros DNA binding in normal murine hematopoietic cells, 26-28 the molecular mechanisms by which Ikaros exerts its tumor suppressor effects in human leukemia ...
SummaryThis study aims to investigate the impact of gestational diabetes mellitus (GDM) on the long-term risks of diabetes in women with prior GDM, including the effect at different time periods after GDM. We searched PubMed and other databases to retrieve articles which were published prior to February 28, 2017. Cohort studies which evaluated the risk and time of onset of diabetes postpartum in women with and without GDM were included. Meta-analysis with random effects models was used to obtain pooled relative risks and 95% confidence intervals for the risk of diabetes. Subgroup analyses were performed to check for different effect sizes as well as consistency across groups. Multivariable logistic regression was used to adjust for confounders. Thirty cohort studies with 2,626,905 pregnant women were included. Women with prior GDM had 7.76-fold (95% confidence intervals: 5.10-11.81) unadjusted pooled risk of diabetes as compared with women without GDM, whilst the adjusted risk was 17. 92-fold (16.96-18.94). The adjusted ORs of GDM for diabetes among women at <3, ≥3 -<6 and ≥6 -<10 years after GDM were 5.37 (3.51-9.34), 16.55 (16.08-17.04) and 8.20 (4.53-14.86), respectively. Women with prior GDM had substantially increased risk of diabetes, with the risk highest during the 3-6 years after GDM.
This study aimed to examine the effect of lifestyle intervention on the risk of gestational diabetes mellitus (GDM). We searched PubMed, Springer and other databases to retrieve articles published in English and Chinese up to 30 September 2015. The inclusion criteria were randomized controlled trials evaluating the effects of lifestyle intervention on risk of GDM. Exclusion criteria were studies with prepregnancy diabetes mellitus or interventions with nutrient supplements. Random-effect and fixed-effect model analyses were used to obtain pooled relative risks and 95% confidence intervals (CIs) of diet and physical activity on the risk of GDM. Subgroup analyses were performed to check the consistency of effect sizes across groups where appropriate. We identified 29 randomized controlled trials with 11,487 pregnant women, addressing the effect of lifestyle intervention on the risk of GDM. In the pooled analysis, either diet or physical activity resulted in an 18% (95%CI 5-30%) reduction in the risk of GDM (P = 0.0091). Subgroup analysis showed that such intervention was effective among women with intervention before the 15th gestational week (relative risk: 0.80, 95%CI 0.66-0.97), but not among women receiving the intervention afterwards. We conclude that lifestyle modification during pregnancy, especially before the 15th gestational week, can reduce the risk of GDM. © 2016 World Obesity.
Ikaros encodes a zinc finger protein that is involved in gene regulation and chromatin remodeling. The majority of Ikaros localizes at pericentromeric heterochromatin (PC-HC) where it regulates expression of target genes. Ikaros function is controlled by posttranslational modification. Phosphorylation of Ikaros by CK2 kinase determines its ability to bind DNA and exert cell cycle control as well as its subcellular localization. We report that Ikaros interacts with protein phosphatase 1 (PP1) via a conserved PP1 binding motif, RVXF, in the C-terminal end of the Ikaros protein. Point mutations of the RVXF motif abolish Ikaros-PP1 interaction and result in decreased DNA binding, an inability to localize to PC-HC, and rapid degradation of the Ikaros protein. The introduction of alanine mutations at CK2-phosphorylated residues increases the half-life of the PP1-nonbinding Ikaros mutant. This suggests that dephosphorylation of these sites by PP1 stabilizes the Ikaros protein and prevents its degradation. In the nucleus, Ikaros forms complexes with ubiquitin, providing evidence that Ikaros degradation involves the ubiquitin/proteasome pathway. In vivo, Ikaros can target PP1 to the nucleus, and a fraction of PP1 colocalizes with Ikaros at PC-HC. These data suggest a novel function for the Ikaros protein; that is, the targeting of PP1 to PC-HC and other chromatin structures. We propose a model whereby the function of Ikaros is controlled by the CK2 and PP1 pathways and that a balance between these two signal transduction pathways is essential for normal cellular function and for the prevention of malignant transformation.
Phospholipase C⑀ (PLC⑀) is a novel class of phosphoinositide-specific PLC characterized by possession of CDC25 homology and Ras/Rap1-associating domains. We and others have shown that human PLC⑀ is translocated from the cytoplasm to the plasma membrane and activated by direct association with Ras at its Ras/Rap1-associating domain. In addition, translocation to the perinuclear region was induced upon association with Rap1⅐GTP. However, the function of the CDC25 homology domain remains to be clarified. Here we show that the CDC25 homology domain of PLC⑀ functions as a guanine nucleotide exchange factor for Rap1 but not for any other Ras family GTPases examined including Rap2 and Ha-Ras. Consistent with this, coexpression of fulllength PLC⑀ or its N-terminal fragment carrying the CDC25 homology domain causes an increase of the intracellular level of Rap1⅐GTP. Concurrently, stimulation of the downstream kinases B-Raf and extracellular signalregulated kinase is observed, whereas the intracellular level of Ras⅐GTP and Raf-1 kinase activity are unaffected. In wild-type Rap1-overexpressing cells, epidermal growth factor induces translocation of PLC⑀ to the perinuclear compartments such as the Golgi apparatus, which is sustained for at least 20 min. In contrast, PLC⑀ lacking the CDC25 domain translocates to the perinuclear compartments only transiently. Further, the formation of Rap1⅐GTP upon epidermal growth factor stimulation exhibits a prolonged time course in cells expressing fulllength PLC⑀ compared with those expressing PLC⑀ lacking the CDC25 homology domain. These results suggest a pivotal role of the CDC25 homology domain in amplifying Rap1-dependent signal transduction, including the activation of PLC⑀ itself, at specific subcellular locations such as the Golgi apparatus.
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