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Jun Chen - One of the best experts on this subject based on the ideXlab platform.

Xinxin Yang - One of the best experts on this subject based on the ideXlab platform.

  • microRNA 15a 16 1 antagomir ameliorates ischemic brain injury in experimental stroke
    Stroke, 2017
    Co-Authors: Xinxin Yang, Sulaiman H Hassan, Anne R Stetler, Xuelian Tang, Jun Chen
    Abstract:

    Background and Purpose—Dysregulation of the miR-15a/16-1 cluster in plasma has been reported in patients with stroke as a potential biomarker for diagnostic and prognostic use. However, the essenti...

  • abstract tp264 microRNA 15a 16 1 antagomir ameliorates ischemic brain injury in experimental stroke
    Stroke, 2017
    Co-Authors: Xinxin Yang, Jun Chen
    Abstract:

    microRNAs (miRs) are small endogenous RNA molecules that repress gene translation by hybridizing to 3’-UTRs of mRNAs. Accumulating evidence has shown that miRs play a critical regulatory role in the pathogenesis of ischemic stroke. MiR-15a and miR-16-1 are two highly conserved miRs, which act similarly by binding to their common mRNA targets, thus forming both a structural and functional cluster. Dysregulated plasma levels of miR-15a/16-1 have been reported in stroke patients. Inhibition of miR-15a has been shown to protect against myocardial infarction and selected by pharmaceutical companies as one of the most attractive miR-based therapeutics. Up to now, the essential role and therapeutic potential of the miR-15a/16-1 cluster in ischemic stroke are poorly understood. In this study, adult male miR-15a/16-1 knockout and wildtype mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) and 72h of reperfusion. In a separate experiment, miR-15a/16-1 specific inhibitor (antagomir, 30 pmol/g) was injected into tail vein of stroke mice and the animals were allowed to survive for 72h. The neurological scores, brain infarct volume, and edema content were then evaluated and analyzed. To explore the underlying mechanism, inflammatory factors were measured by qPCR or ELISA and anti-apoptotic proteins were examined by western blotting. We found that genetic deletion of miR-15a/16-1 or intravenous delivery of miR-15a/16-1 antagomir significantly reduced cerebral infarct size, decreased brain edema and improved neurological outcomes in stroke mice. Mechanistically, treatment of miR-15a/16-1 antagomir significantly ameliorated the expression of several key inflammatory factors and increased the Bcl-2 and Bcl-w levels in the ischemic brain regions. These results demonstrated that pharmacological inhibition of miR-15a/16-1 reduces ischemic brain injury via both anti-apoptotic and anti-inflammatory mechanisms and the miR-15a/16-1 cluster is a novel therapeutic target for ischemic stroke.

  • abstract tp264 microRNA 15a 16 1 antagomir ameliorates ischemic brain injury in experimental stroke
    Stroke, 2017
    Co-Authors: Xinxin Yang, Jun Chen, Kai Liu, Ke-jie Yin
    Abstract:

    microRNAs (miRs) are small endogenous RNA molecules that repress gene translation by hybridizing to 3’-UTRs of mRNAs. Accumulating evidence has shown that miRs play a critical regulatory role in th...

Ke-jie Yin - One of the best experts on this subject based on the ideXlab platform.

Alan M Gewirtz - One of the best experts on this subject based on the ideXlab platform.

  • the c myb proto oncogene and microRNA 15a comprise an active autoregulatory feedback loop in human hematopoietic cells
    Blood, 2009
    Co-Authors: Huiwu Zhao, Anna Kalota, Alan M Gewirtz
    Abstract:

    The c-myb proto-oncogene encodes an obligate hematopoietic cell transcription factor important for lineage commitment, proliferation, and differentiation. Given its critical functions, c-Myb regulatory factors are of great interest but remain incompletely defined. Herein we show that c-Myb expression is subject to posttranscriptional regulation by microRNA (miRNA)–15a. Using a luciferase reporter assay, we found that miR-15a directly binds the 3′-UTR of c-myb mRNA. By transfecting K562 myeloid leukemia cells with a miR-15a mimic, functionality of binding was shown. The mimic decreased c-Myb expression, and blocked the cells in the G1 phase of cell cycle. Exogenous expression of c-myb mRNA lacking the 3′-UTR partially rescued the miR-15a induced cell-cycle block. Of interest, the miR-15a promoter contained several potential c-Myb protein binding sites. Occupancy of one canonical c-Myb binding site was demonstrated by chromatin immunoprecipitation analysis and shown to be required for miR-15a expression in K562 cells. Finally, in studies using normal human CD34+ cells, we showed that c-Myb and miR-15a expression were inversely correlated in cells undergoing erythroid differentiation, and that overexpression of miR-15a blocked both erythroid and myeloid colony formation in vitro. In aggregate, these findings suggest the presence of a c-Myb–miR-15a autoregulatory feedback loop of potential importance in human hematopoiesis.

  • the c myb proto oncogene and microRNA 15a comprise an active autoregulatory feedback loop in human hematopoietic cells
    Blood, 2009
    Co-Authors: Huiwu Zhao, Anna Kalota, Alan M Gewirtz, Shenghao Jin
    Abstract:

    The c-myb proto-oncogene encodes an obligate hematopoietic cell transcription factor important for lineage commitment, proliferation, and differentiation. Given its critical functions, c-Myb regulatory factors are of great interest but remain incompletely defined. Herein we show that c-Myb expression is subject to posttranscriptional regulation by microRNA (miRNA)-15a. Using a luciferase reporter assay, we found that miR-15a directly binds the 3'-UTR of c-myb mRNA. By transfecting K562 myeloid leukemia cells with a miR-15a mimic, functionality of binding was shown. The mimic decreased c-Myb expression, and blocked the cells in the G(1) phase of cell cycle. Exogenous expression of c-myb mRNA lacking the 3'-UTR partially rescued the miR-15a induced cell-cycle block. Of interest, the miR-15a promoter contained several potential c-Myb protein binding sites. Occupancy of one canonical c-Myb binding site was demonstrated by chromatin immunoprecipitation analysis and shown to be required for miR-15a expression in K562 cells. Finally, in studies using normal human CD34(+) cells, we showed that c-Myb and miR-15a expression were inversely correlated in cells undergoing erythroid differentiation, and that overexpression of miR-15a blocked both erythroid and myeloid colony formation in vitro. In aggregate, these findings suggest the presence of a c-Myb-miR-15a autoregulatory feedback loop of potential importance in human hematopoiesis.

Diego Ingrosso - One of the best experts on this subject based on the ideXlab platform.

  • the microRNA 15a 16 1 cluster down regulates protein repair isoaspartyl methyltransferase in hepatoma cells implications for apoptosis regulation
    Journal of Biological Chemistry, 2011
    Co-Authors: Irene Sambri, Rosanna Capasso, Piero Pucci, Alessandra F. Perna, Diego Ingrosso
    Abstract:

    Abstract Asparaginyl deamidation, a spontaneous protein post-biosynthetic modification, determines isoaspartyl formation and structural-functional impairment. The i s o a s p a r t y l p ro t e i n c a r b o x y l - O -methyltransferase (PCMT; EC 2.1.1.77) catalyzes the repair of the isopeptide bonds at isoaspartyl sites, preventing deamidationrelated functional impairment. Protein deamidation affects key apoptosis mediators, such as BclxL, thus increasing susceptibility to apoptosis, while PCMT activity may effectively counteract such alterations. Aims of this work was to establish the role of RNAi as a potential mechanism for regulating PCMT expression and its possible implications in apoptosis. We investigated the regulatory properties of miR15a/16-1 cluster on PCMT expression on HepG2 cells. MiR15a or 16-1 transfection, as well their relevant antagonists, showed that PCMT is effectively regulated by this miRNA cluster. The direct interaction of these two miRNAs with the seed sequence at the 3 UTR of PCMT transcripts was demonstrated by luciferase assay system. The role of PCMT downre g u l a t i o n i n conditiong t h e susceptibility to apoptosis was investigated by using various specific snRNA approaches, in order to prevent non PCMT specific pleiotropic effects to take place. We found that PCMT silencing is associated with an increase of the BclxL isoform which has been reported to be inactivated by deamidation, thus making cells more susceptible to apoptosis induced by cisplatinum. We conclude that PCMT is effectively regulated by the miR15a-16-1 cluster and is involved in apoptosis by preserving the structural stability and biological function of BclxL from deamidation. Control of PCMT expression by snRNAs may thus represent a late check point in apoptosis regulation.

  • the microRNA 15a 16 1 cluster down regulates protein repair isoaspartyl methyltransferase in hepatoma cells implications for apoptosis regulation
    Journal of Biological Chemistry, 2011
    Co-Authors: Irene Sambri, Rosanna Capasso, Piero Pucci, Alessandra F. Perna, Diego Ingrosso
    Abstract:

    Asparaginyl deamidation, a spontaneous protein post-biosynthetic modification, determines isoaspartyl formation and structure-function impairment. The isoaspartyl protein carboxyl-O-methyltransferase (PCMT1; EC 2.1.1.77) catalyzes the repair of the isopeptide bonds at isoaspartyl sites, preventing deamidation-related functional impairment. Protein deamidation affects key apoptosis mediators, such as BclxL, thus increasing susceptibility to apoptosis, whereas PCMT1 activity may effectively counteract such alterations. The aim of this work was to establish the role of RNAi as a potential mechanism for regulating PCMT1 expression and its possible implications in apoptosis. We investigated the regulatory properties of the microRNA 15a/16–1 cluster on PCMT1 expression on HepG2 cells. microRNA 15a or microRNA 16–1 transfection, as well as their relevant antagonists, showed that PCMT1 is effectively regulated by this microRNA cluster. The direct interaction of these two microRNAs with the seed sequence at the 3′ UTR of PCMT1 transcripts was demonstrated by the luciferase assay system. The role of PCMT1 down-regulation in conditioning the susceptibility to apoptosis was investigated using various specific siRNA or shRNA approaches, to prevent non-PCMT1-specific pleiotropic effects to take place. We found that PCMT1 silencing is associated with an increase of the BclxL isoform reported to be inactivated by deamidation, thus making cells more susceptible to apoptosis induced by cisplatinum. We conclude that PCMT1 is effectively regulated by the microRNA 15a/16–1 cluster and is involved in apoptosis by preserving the structural stability and biological function of BclxL from deamidation. Control of PCMT1 expression by microRNA 15a/16–1 may thus represent a late checkpoint in apoptosis regulation.