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1.  S6K1 determines the metabolic requirements for BCR-ABL survival 
Oncogene  2012;32(4):453-461.
In Chronic Myelogenous Leukemia, the constitutive activation of the BCR-ABL kinase transforms cells to an “addicted” state that requires glucose metabolism for survival. We investigated S6K1, a protein kinase that drives glycolysis in leukemia cells, as a target for counteracting glucose-dependent survival induced by BCR-ABL. BCR-ABL potently activated S6K1-dependent signaling and glycolysis. Although S6K1 knockdown or rapamycin treatment suppressed glycolysis in BCR-ABL transformed cells, these treatments did not induce cell death. Instead, loss of S6K1 triggered compensatory activation of fatty acid oxidation, a metabolic program that can support glucose-independent cell survival. Fatty acid oxidation in response to S6K1-inactivation required the expression of the fatty acid transporter Cpt1c, which was recently linked to rapamycin resistance in cancer. Finally, addition of an inhibitor of fatty acid oxidation significantly enhanced cytotoxicity in response to S6K1 inactivation. These data indicate that S6K1 dictates the metabolic requirements mediating BCR-ABL survival and provide a rationale for combining targeted inhibitors of signal transduction with strategies to interrupt oncogene-induced metabolism.
PMCID: PMC3371300  PMID: 22391570
S6K1; glycolysis; fatty acid oxidation; rapamycin; leukemia; Cpt1c
2.  MiR-590-5P Inhibits Growth of HepG2 Cells via Decrease of S100A10 Expression and Inhibition of the Wnt Pathway 
Hepatocellular carcinoma is one of the most common and lethal cancers worldwide, especially in developing countries. In the present study, we found that the expression of a microRNA, miR-590-5P, was down-regulated and S100A10 was up-regulated in six hepatocellular carcinoma cell lines. The reporter gene assay showed that overexpression of miR-590-5P effectively reduced the activity of luciferase expressed by a vector bearing the 3′ untranslated region of S100A10 mRNA. Ectopic miR-590-5P overexpression mediated by lentiviral infection decreased expression of S100A10. Infection of Lv-miR-590-5P inhibited cell growth and induced cell cycle G1 arrest in HepG2 cells. In addition, miR-590-5P expression suppressed the expression of Wnt5a, cMyc and cyclin D1, and increased the phosphorylation of β-catenin and expression of Caspase 3, which may contribute to the inhibitory effect of miR-590-5P on cell growth. Taken together, our data suggest that down-regulation of miR-590-5P is involved in hepatocellular carcinoma and the restoration of miR-590-5P can impair the growth of cancer cells, suggesting that miR-590-5P may be a potential target molecule for the therapy of hepatocellular carcinoma.
PMCID: PMC3645761  PMID: 23598417
miR-590-5P; S100A10; hepatocellular carcinoma; Wnt pathway; lentiviral system; reporter gene
3.  Distinct regulation of murine lupus susceptibility genes by the IRF5-Blimp-1 axis 
Genome-wide association studies have identified lupus susceptibility genes such as IRF5 and PRDM1 (encoding for the IRF5 and Blimp-1) in the human genome. Accordingly, the murine Irf5 and Prdm1 genes have been shown to play a role in lupus susceptibility. However, it remains unclear how IRF5 and Blimp-1 (a transcriptional target of IRF5) contribute to lupus susceptibility. Given that the murine lupus susceptibility locus Nba2 includes the interferon-regulated genes Ifi202 (encoding for the p202 protein), Aim2 (encoding for the Aim2 protein), and Fcgr2b (encoding for the FcγRIIB receptor), we investigated whether the IRF5-Blimp-1 axis could regulate the expression of these genes. We found that an Irf5-deficiency in mice decreased the expression of Blimp-1 and reduced the expression of the Ifi202. However, the deficiency increased the expression of Aim2 and Fcgr2b. Correspondingly, increased expression of IRF5 in cells increased levels of Blimp-1 and p202 protein. Moreover, Blimp-1 expression increased the expression of Ifi202, whereas it reduced the expression of Aim2. Interestingly, an Aim2-deficiency in female mice increased the expression of IRF5. Similarly, the Fcgr2b-deficient mice expressed increased levels of IRF5. Moreover, increased expression of IRF5 and Blimp-1 in lupus-prone B6.Nba2, NZB, and B6.Sle123 female mice (as compared to age-matched C57BL/6 female mice) was associated with increased levels of the p202 protein. Together, our observations demonstrate that the IRF5-Blimp-1 axis differentially regulates the expression of Nba2 lupus susceptibility genes, and suggest an important role for the IRF5-Blimp-1-p202 axis in murine lupus susceptibility.
PMCID: PMC3244553  PMID: 22116829
IRF5; Blimp-1; Nba2 locus; p202; interferon; autoimmunity; SLE
4.  Emerging Roles for the Interferon-Inducible p200-Family Proteins in Sex Bias in Systemic Lupus Erythematosus 
Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple organs. The disease is characterized by the production of pathogenic autoantibodies to DNA and certain nuclear antigens, chronic inflammation, and immune dysregulation. Genetic studies involving SLE patients and mouse models have indicated that multiple lupus susceptible genes contribute to the disease phenotype. Notably, the development of SLE in patients and in certain mouse models exhibits a strong sex bias. In addition, several lines of evidence indicates that activation of interferon-α (IFN-α) signaling in immune cells and alterations in the expression of certain immunomodulatory cytokines contribute to lupus pathogenesis. Studies have implicated factors, such as the X chromosomal gene dosage effect and the sex hormones, in gender bias in SLE. However, the molecular mechanisms remain unclear. Additionally, it remains unclear whether these factors influence the “IFN-signature,” which is associated with SLE. In this regard, a mutually positive regulatory feedback loop between IFNs and estrogen receptor-α (ERα) has been identified in immune cells. Moreover, studies indicate that the expression of certain IFN-inducible p200-family proteins that act as innate immune sensors for cytosolic DNA is differentially regulated by sex hormones. In this review, we discuss how the modulation of the expression of the p200-family proteins in immune cells by sex hormones and IFNs contributes to sex bias in SLE. An improved understanding of the regulation and roles of the p200-family proteins in immune cells is critical to understand lupus pathogenesis as well as response (or the lack of it) to various therapies.
PMCID: PMC3234491  PMID: 21902548
5.  A Novel Genotype H9N2 Influenza Virus Possessing Human H5N1 Internal Genomes Has Been Circulating in Poultry in Eastern China since 1998 ▿ †  
Journal of Virology  2009;83(17):8428-8438.
Many novel reassortant influenza viruses of the H9N2 genotype have emerged in aquatic birds in southern China since their initial isolation in this region in 1994. However, the genesis and evolution of H9N2 viruses in poultry in eastern China have not been investigated systematically. In the current study, H9N2 influenza viruses isolated from poultry in eastern China during the past 10 years were characterized genetically and antigenically. Phylogenetic analysis revealed that these H9N2 viruses have undergone extensive reassortment to generate multiple novel genotypes, including four genotypes (J, F, K, and L) that have never been recognized before. The major H9N2 influenza viruses represented by A/Chicken/Beijing/1/1994 (Ck/BJ/1/94)-like viruses circulating in poultry in eastern China before 1998 have been gradually replaced by A/Chicken/Shanghai/F/1998 (Ck/SH/F/98)-like viruses, which have a genotype different from that of viruses isolated in southern China. The similarity of the internal genes of these H9N2 viruses to those of the H5N1 influenza viruses isolated from 2001 onwards suggests that the Ck/SH/F/98-like virus may have been the donor of internal genes of human and poultry H5N1 influenza viruses circulating in Eurasia. Experimental studies showed that some of these H9N2 viruses could be efficiently transmitted by the respiratory tract in chicken flocks. Our study provides new insight into the genesis and evolution of H9N2 influenza viruses and supports the notion that some of these viruses may have been the donors of internal genes found in H5N1 viruses.
PMCID: PMC2738149  PMID: 19553328

Results 1-5 (5)