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  • 1
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    Sirt6 Improves Reprogramming Efficiency in Older Human Cells [Molecular Bases of Disease] (2013)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2013-06-22
    Description: Aging is known to be the single most important risk factor for multiple diseases. Sirtuin 6, or SIRT6, has recently been identified as a critical regulator of transcription, genome stability, telomere integrity, DNA repair, and metabolic homeostasis. A knockout mouse model of SIRT6 has displayed dramatic phenotypes of accelerated aging. In keeping with its role in aging, we demonstrated that human dermal fibroblasts (HDFs) from older human subjects were more resistant to reprogramming by classic Yamanaka factors than those from younger human subjects, but the addition of SIRT6 during reprogramming improved such efficiency in older HDFs substantially. Despite the importance of SIRT6, little is known about the molecular mechanism of its regulation. We show, for the first, time posttranscriptional regulation of SIRT6 by miR-766 and inverse correlation in the expression of this microRNA in HDFs from different age groups. Our results suggest that SIRT6 regulates miR-766 transcription via a feedback regulatory loop, which has implications for the modulation of SIRT6 expression in reprogramming of aging cells.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 2
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    ERK Phosphorylates HDAC6 [Signal Transduction] (2013)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
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    Publication Date: 2013-11-16
    Description: Histone deacetylase 6 (HDAC6) is well known for its ability to promote cell migration through deacetylation of its cytoplasmic substrates such as α-tubulin. However, how HDAC6 itself is regulated to control cell motility remains elusive. Previous studies have shown that one third of extracellular signal-regulated kinase (ERK) is associated with the microtubule cytoskeleton in cells. Yet, no connection between HDAC6 and ERK has been discovered. Here, for the first time, we reveal that ERK binds to and phosphorylates HDAC6 to promote cell migration via deacetylation of α-tubulin. We have identified two novel ERK-mediated phosphorylation sites: threonine 1031 and serine 1035 in HDAC6. Both sites were phosphorylated by ERK1 in vitro, whereas Ser-1035 was phosphorylated in response to the activation of EGFR-Ras-Raf-MEK-ERK signaling pathway in vivo. HDAC6-null mouse embryonic fibroblasts rescued by the nonphosphorylation mimicking mutant displayed significantly reduced cell migration compared with those rescued by the wild type. Consistently, the nonphosphorylation mimicking mutant exerted lower tubulin deacetylase activity in vivo compared with the wild type. These data indicate that ERK/HDAC6-mediated cell motility is through deacetylation of α-tubulin. Overall, our results suggest that HDAC6-mediated cell migration could be governed by EGFR-Ras-Raf-MEK-ERK signaling.
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    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 3
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    Crystal Structure of Second Extended PHD of Human PHF6 [Gene Regulation] (2014)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2014-04-05
    Description: The plant homeodomain finger 6 (PHF6) was originally identified as the gene mutated in the X-linked mental retardation disorder Börjeson-Forssman-Lehmann syndrome. Mutations in the PHF6 gene have also been associated with T-cell acute lymphoblastic leukemia and acute myeloid leukemia. Approximately half of the disease-associated mutations are distributed in the second conserved extended plant homeodomain (ePHD2) of PHF6, indicating the functional importance of the ePHD2 domain. Here, we report the high resolution crystal structure of the ePHD2 domain of PHF6, which contains an N-terminal pre-PHD (C2HC zinc finger), a long linker, and an atypical PHD finger. PHF6-ePHD2 appears to fold as a novel integrated structural module. Structural analysis of PHF6-ePHD2 reveals pathological implication of PHF6 gene mutations in Börjeson-Forssman-Lehmann syndrome, T-cell acute lymphoblastic leukemia, and acute myeloid leukemia. The binding experiments show that PHF6-ePHD2 can bind dsDNA but not histones. We also demonstrate PHF6 protein directly interacts with the nucleosome remodeling and deacetylation complex component RBBP4. Via this interaction, PHF6 exerts its transcriptional repression activity. Taken together, these data support the hypothesis that PHF6 may function as a transcriptional repressor using its ePHD domains binding to the promoter region of its repressed gene, and this process was regulated by the nucleosome remodeling and deacetylation complex that was recruited to the genomic target site by NoLS region of PHF6.
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    Topics: Biology , Chemistry and Pharmacology
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  • 4
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    HO-1 Suppresses Th17-mediated Neutrophilic Airway Inflammation [Immunology] (2013)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
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    Publication Date: 2013-11-30
    Description: Allergic asthma is conventionally considered as a Th2 immune response characterized by eosinophilic inflammation. Recent investigations revealed that Th17 cells play an important role in the pathogenesis of non-eosinophilic asthma (NEA), resulting in steroid-resistant neutrophilic airway inflammation. Heme oxygenase-1 (HO-1) has anti-inflammation, anti-oxidation, and anti-apoptosis functions. However, its role in NEA is still unclear. Here, we explore the role of HO-1 in a mouse model of NEA. HO-1 inducer hemin or HO-1 inhibitor tin protoporphyrin IX was injected intraperitoneally into ovalbumin-challenged DO11.10 mice. Small interfering RNA (siRNA) was delivered into mice to knock down HO-1 expression. The results show that induction of HO-1 by hemin attenuated airway inflammation and decreased neutrophil infiltration in bronchial alveolar lavage fluid and was accompanied by a lower proportion of Th17 cells in mediastinal lymph nodes and spleen. More importantly, induction of HO-1 down-regulated Th17-related transcription factor retinoic acid-related orphan receptor γt (RORγt) expression and decreased IL-17A levels, all of which correlated with a decrease in phosphorylated STAT3 (p-STAT3) level and inhibition of Th17 cell differentiation. Consistently, the above events could be reversed by tin protoporphyrin IX. Also, HO-1 siRNA transfection abolished the effect of hemin induced HO-1 in vivo. Meanwhile, the hemin treatment promoted the level of Foxp3 expression and enhanced the proportion of regulatory T cells (Tregs). Collectively, our findings indicate that HO-1 exhibits anti-inflammatory activity in the mouse model of NEA via inhibition of the p-STAT3-RORγt pathway, regulating kinetics of RORγt and Foxp3 expression, thus providing a possible novel therapeutic target in asthmatic patients.
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    Topics: Biology , Chemistry and Pharmacology
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  • 5
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    A Novel Function of JMJD5 in Mitotic Process [Cell Biology] (2016)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2016-02-27
    Description: Precise mitotic spindle assembly is a guarantee of proper chromosome segregation during mitosis. Chromosome instability caused by disturbed mitosis is one of the major features of various types of cancer. JMJD5 has been reported to be involved in epigenetic regulation of gene expression in the nucleus, but little is known about its function in mitotic process. Here we report the unexpected localization and function of JMJD5 in mitotic progression. JMJD5 partially accumulates on mitotic spindles during mitosis, and depletion of JMJD5 results in significant mitotic arrest, spindle assembly defects, and sustained activation of the spindle assembly checkpoint (SAC). Inactivating SAC can efficiently reverse the mitotic arrest caused by JMJD5 depletion. Moreover, JMJD5 is found to interact with tubulin proteins and associate with microtubules during mitosis. JMJD5-depleted cells show a significant reduction of α-tubulin acetylation level on mitotic spindles and fail to generate enough interkinetochore tension to satisfy the SAC. Further, JMJD5 depletion also increases the susceptibility of HeLa cells to the antimicrotubule agent. Taken together, these results suggest that JMJD5 plays an important role in regulating mitotic progression, probably by modulating the stability of spindle microtubules.
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    Topics: Biology , Chemistry and Pharmacology
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  • 6
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    GLI2 Interacts with GCMa in Syncytialization [Signal Transduction] (2016)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
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    Publication Date: 2016-03-12
    Description: Cell-cell fusion of human villous trophoblasts, referred to as a process of syncytialization, acts as a prerequisite for the proper development and functional maintenance of the human placenta. Given the fact that the main components of the Hedgehog signaling pathway are expressed predominantly in the syncytial layer of human placental villi, in this study, we investigated the potential roles and underlying mechanisms of Hedgehog signaling in trophoblastic fusion. Activation of Hedgehog signaling by a variety of approaches robustly induced cell fusion and the expression of syncytial markers, whereas suppression of Hedgehog signaling significantly attenuated cell fusion and the expression of syncytial markers in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in Hedgehog signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated Hedgehog-induced cell fusion, whereas overexpression of the GLI2 activator alone was sufficient to induce cell fusion. Finally, GLI2 not only stabilized glial cell missing-a, a pivotal transcriptional factor for trophoblastic syncytialization, but also formed a transcriptional heterodimer with glial cell missing-a to transactivate syncytin-1, a trophoblastic fusogen, and promote trophoblastic syncytialization. Taken together, this study uncovered a so far uncharacterized role of Hedgehog/GLI2 signaling in trophoblastic fusion, implicating that Hedgehog signaling, through GLI2, could be required for human placental development and pregnancy maintenance.
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    Topics: Biology , Chemistry and Pharmacology
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  • 7
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    MitoNEET and Experimental Alcoholic Steatohepatitis [Metabolism] (2016)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2016-10-22
    Description: MitoNEET (mNT) (CDGSH iron-sulfur domain-containing protein 1 or CISD1) is an outer mitochondrial membrane protein that donates 2Fe-2S clusters to apo-acceptor proteins. In the present study, using a global mNT knock-out (mNTKO) mouse model, we investigated the in vivo functional role of mNT in the development of alcoholic steatohepatitis. Experimental alcoholic steatohepatitis was achieved by pair feeding wild-type (WT) and mNTKO mice with Lieber-DeCarli ethanol-containing diets for 4 weeks. Strikingly, chronically ethanol-fed mNTKO mice were completely resistant to ethanol-induced steatohepatitis as revealed by dramatically reduced hepatic triglycerides, decreased hepatic cholesterol level, diminished liver inflammatory response, and normalized serum ALT levels. Mechanistic studies demonstrated that ethanol administration to mNTKO mice induced two pivotal endocrine hormones, namely, adipose-derived adiponectin and gut-derived fibroblast growth factor 15 (Fgf15). The elevation in circulating levels of adiponectin and Fgf15 led to normalized hepatic and serum levels of bile acids, limited hepatic accumulation of toxic bile, attenuated inflammation, and amelioration of liver injury in the ethanol-fed mNTKO mice. Other potential mechanisms such as reduced oxidative stress, activated Sirt1 signaling, and diminished NF-κB activity also contribute to hepatic improvement in the ethanol-fed mNTKO mice. In conclusion, the present study identified adiponectin and Fgf15 as pivotal adipose-gut-liver metabolic coordinators in mediating the protective action of mNT deficiency against development of alcoholic steatohepatitis in mice. Our findings may help to establish mNT as a novel therapeutic target and pharmacological inhibition of mNT may be beneficial for the prevention and treatment of human alcoholic steatohepatitis.
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    Topics: Biology , Chemistry and Pharmacology
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  • 8
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    PLK1 Antagonizes SUMO Conjugation to FoxM1b [Gene Regulation] (2015)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2015-02-07
    Description: Transcription factor Forkhead box protein M1b (FoxM1b) plays an important role during mitotic entry and progression. Our previous studies identified polo-like kinase 1 (PLK1) as a major regulator of FoxM1b. During G2/M transition, PLK1 directly interacts with and phosphorylates FoxM1b, resulting in full activation of the transactivation capacity of FoxM1b. Such a vital regulatory mechanism is essential for timely mitotic entry and progression. However, the molecular mechanism by which PLK1-mediated phosphorylation enhances the transcriptional activity of FoxM1b remains to be determined. We demonstrate that FoxM1b can be SUMOylated in vitro and in vivo, preferentially by SUMO-1. SUMOylation of FoxM1b was found to occur at multiple sites, leading to suppression of FoxM1b transcriptional activity. Such a posttranslational modification of FoxM1b was antagonized by PLK1-mediated phosphorylation. By immunofluorescence staining and subcellular fractionation, we demonstrate that SUMO conjugation promotes cytosolic translocation of FoxM1b. Moreover, SUMO modification of FoxM1b facilitates the ubiquitin-mediated proteasomal degradation of FoxM1b. PLK1-mediated phosphorylation of FoxM1b abrogates the inhibitory effect on FoxM1b by SUMO modification, thereby promoting its nuclear translocation and preventing its proteolytic degradation in the cytoplasm. Such an antagonistic regulatory mechanism is essential for the mitotic function of FoxM1b, ensuring timely mitotic entry and progression. Taken together, our studies have revealed a working mechanism by which PLK1 positively regulates the activity and level of FoxM1b, which would greatly facilitate therapeutic interventions that focus on targeting the PLK1-mediated and/or FoxM1-mediated signaling network.
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    Topics: Biology , Chemistry and Pharmacology
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  • 9
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    Structure of the ARAP3-RhoGAP{middle dot}RhoA Complex [Enzymology] (2016)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2016-08-06
    Description: ARAP3 (Arf-GAP with Rho-GAP domain, ANK repeat, and PH domain-containing protein 3) is unique for its dual specificity GAPs (GTPase-activating protein) activity for Arf6 (ADP-ribosylation factor 6) and RhoA (Ras homolog gene family member A) regulated by phosphatidylinositol 3,4,5-trisphosphate and a small GTPase Rap1-GTP and is involved in regulation of cell shape and adhesion. However, the molecular interface between the ARAP3-RhoGAP domain and RhoA is unknown, as is the substrates specificity of the RhoGAP domain. In this study, we solved the crystal structure of RhoA in complex with the RhoGAP domain of ARAP3. The structure of the complex presented a clear interface between the RhoGAP domain and RhoA. By analyzing the crystal structure and in combination with in vitro GTPase activity assays and isothermal titration calorimetry experiments, we identified the crucial residues affecting RhoGAP activity and substrates specificity among RhoA, Rac1 (Ras-related C3 botulinum toxin substrate 1), and Cdc42 (cell division control protein 42 homolog).
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    Topics: Biology , Chemistry and Pharmacology
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  • 10
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    Biochemical and Biological Function of Top2-Mus101 Interaction [Enzymology] (2016)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
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    Publication Date: 2016-06-18
    Description: Eukaryotic topoisomerase 2 (Top2) and one of its interacting partners, topoisomerase IIβ binding protein 1 (TopBP1) are two proteins performing essential cellular functions. We mapped the interacting domains of these two proteins using co-immunoprecipitation and pulldown experiments with truncated or mutant Drosophila Top2 with various Ser-to-Ala substitutions. We discovered that the last 20 amino acids of Top2 represent the key region for binding with Mus101 (the Drosophila homolog of TopBP1) and that phosphorylation of Ser-1428 and Ser-1443 is important for Top2 to interact with the N terminus of Mus101, which contains the BRCT1/2 domains. The interaction between Mus101 and the Top2 C-terminal regulatory domain is phosphorylation-dependent because treatment with phosphatase abolishes their association in pulldown assays. The binding affinity of N-terminal Mus101 with a synthetic phosphorylated peptide spanning the last 25 amino acids of Top2 (with Ser(P)-1428 and Ser(P)-1443) was determined by surface plasmon resonance with a Kd of 0.57 μm. In an in vitro decatenation assay, Mus101 can specifically reduce the decatenation activity of Top2, and dephosphorylation of Top2 attenuates this response. Next, we endeavored to establish a cellular system for testing the biological function of Top2-Mus101 interaction. Top2-silenced S2 cells rescued by Top2Δ20, Top2 with 20 amino acids truncated from the C terminus, developed abnormally high chromosome numbers, which implies that Top2-Mus101 interaction is important for maintaining the fidelity of chromosome segregation during mitosis.
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    Topics: Biology , Chemistry and Pharmacology
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