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Articles by S Liu
Total Records ( 15 ) for S Liu
  S Liu , K Kang , J Zhang , Q Ouyang , Z Zhou , S Tian and M. Xing
 

A 1591-bp cDNA of a serine-rich protein kinase (SRPK)-like protein has been identified in Physarum polycephalum (GenBank accession No. DQ140379). The cDNA contains two repeat sequences at bp 1–153 and bp 395–547. The encoding sequence is 56% homologous to human SRPK1 and is named Physarum SRPK (PSRPK). Consistent with other SRPKs, the consensus motifs of PSRPK are within the two conserved domains (CDs). However, divergent motifs between the N-terminal and CDs are much shorter than the corresponding sequences of other SRPKs. To study the structure and function of this protein, we performed co-expression experiment in Escherichia coli and in vitro phosphorylation assay to investigate the phosphorylation effect of recombinant PSRPK on the human SR protein, ASF/SF2. Western blot analysis showed that PSRPK could phosphorylate ASF/SF2 in E. coli cells. Autoradiographic examination showed that both recombinant PSRPK and a truncated form of PSRPK with a 28-aa deletion at the N-terminus could phosphorylate ASF/SF2 and a truncated form of ASF/SF2 that contains the RS domain. However, these two forms of PSRPK could not phosphorylate a truncated form ASF/SF2 that lacks the RS domain. A truncated form of PSRPK that lacks either of CDs does not have any phosphorylation activity. These results indicated that, like other SRPKs, the phosphorylation site in PSRPK is located within the RS domain of the SR protein and that its phosphorylation activity is closely associated with the two CDs. This study on the structure and function of PSRPK demonstrates that it is a new member of the SRPK family.

  I Tabbi Anneni , R Cooksey , V Gunda , S Liu , A Mueller , G Song , D. A McClain and L. Wang
 

The orphan nuclear receptor small heterodimer partner (SHP) regulates metabolic pathways involved in hepatic bile acid production and both lipid and glucose homeostasis via the transcriptional repression of other nuclear receptors. In the present study, we generated fat-specific SHP-overexpressed transgenic (TG) mice and determined the potential role of SHP activation, specifically in adipocytes, in the regulation of adipose tissue function in response to stressors. We determined in 2 mo-old SHP TG mice body weight, fat mass index, adipose tissues morphology, thermogenic and metabolic gene expression, metabolic rates at baseline and in response to β adrenergic receptor agonists, and brown fat ultrastructural changes in response to cold exposure (6–48 h). Mice were fed a 10-wk high-fat diet (HFD; 42% fat). Weight gain, fat mass index, adipose tissues morphology, glucose tolerance, and metabolic rates were determined at the end of the feeding. Young TG mice had increased body weight and adiposity; however, their energy metabolism was increased and brown fat function was enhanced in response to cold exposure through the activation of thermogenic genes and mitochondrial biogenesis. SHP overexpression exacerbated the diet-induced obesity phenotype as evidence by marked weight gain over time, increased adiposity, and severe glucose intolerance compared with wild-type mice fed a HFD. In addition, SHP-TG mice fed HFD had decreased diet-induced adaptive thermogenesis, increased food intake, and decreased physical activity. In conclusion, SHP activation in adipocytes strongly affects weight gain and diet-induced obesity. Developing a synthetic compound to antagonize the effect of SHP may prove to be useful in treating obesity.

  L He , H Zeng , F Li , J Feng , S Liu , J Liu , J Yu , J Mao , T Hong , A. F Chen , X Wang and G. Wang
 

Hyperhomocysteinemia (HHcy) has been associated with impaired vascular endothelial function. Our previous study demonstrated significantly higher secretion of the chemokine monocyte chemoattractant protein-1 from monocytes in response to lipopolysaccharide in patients with HHcy. In the present study, we investigated whether coronary endothelial function was damaged in patients with chronic HHcy (plasma level of homocysteine >15 µmol/l) and, if so, whether this impaired endothelial function is induced by the uncoupling of endothelial nitric oxide synthase (eNOS). When tetrahydrobiopterin levels are inadequate, eNOS is no longer coupled to l-arginine oxidation, which results in reactive oxygen species rather than nitric oxide production, thereby inducing vascular endothelial dysfunction. The 71 participants were divided into two groups, control (n = 50) and HHcy (n = 21). Quantification of coronary flow velocity reserve (CFVR) was after rest and after adenosine administration done by noninvasive Doppler echocardiography. Plasma levels of nitric oxide and tetrahydrobiopterin were significantly lower in patients with HHcy than in controls (99.54 ± 32.23 vs. 119.50 ± 37.68 µmol/l and 1.43 ± 0.46 vs. 1.73 ± 0.56 pmol/ml, all P < 0.05). Furthermore, CFVR was significantly lower in the HHcy than the control group (2.76 ± 0.49 vs. 3.09 ± 0.52, P < 0.05). In addition, plasma level of homocysteine was negatively correlated with CFVR. Chronic HHcy may contribute to coronary artery disease by inducing dysfunction of the coronary artery endothelium. The uncoupling of eNOS induced by HHcy in patients with chronic HHcy may explain this adverse effect in part.

  R Garzon , S Liu , M Fabbri , Z Liu , C. E.A Heaphy , E Callegari , S Schwind , J Pang , J Yu , N Muthusamy , V Havelange , S Volinia , W Blum , L. J Rush , D Perrotti , M Andreeff , C. D Bloomfield , J. C Byrd , K Chan , L. C Wu , C. M Croce and G. Marcucci
 

Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs. Recently, miRNAs have been shown to play a role as both targets and effectors in gene hypermethylation and silencing in malignant cells. In the current study, we showed that enforced expression of miR-29b in acute myeloid leukemia cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at both RNA and protein levels. This in turn led to decrease in global DNA methylation and reexpression of p15INK4b and ESR1 via promoter DNA hypomethylation. Although down-regulation of DNMT3A and DNMT3B was the result of a direct interaction of miR-29b with the 3' untranslated regions of these genes, no predicted miR-29b interaction sites were found in the DNMT1 3' untranslated regions. Further experiments revealed that miR-29b down-regulates DNMT1 indirectly by targeting Sp1, a transactivator of the DNMT1 gene. Altogether, these data provide novel functional links between miRNAs and aberrant DNA hypermethylation in acute myeloid leukemia and suggest a potentially therapeutic use of synthetic miR-29b oligonucleotides as effective hypomethylating compounds.

  Y He , H Zhang , J Yin , J Xie , X Tan , S Liu , Q Zhang , C Li , J Zhao , H Wang and G. Cao
 

Genetic predisposition of nuclear factor-kappa B (NF-B)-signaling pathways linking inflammation to hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remains unresolved. We conducted a case–control study to determine the associations of the polymorphisms within the promoter regions of NFKB1 encoding NF-B1 and NFKBIA encoding IkappaBalpha with the development of HCC. A total of 404 healthy controls, 482 non-HCC subjects with HBV infection and 202 patients with HCC were included. NFKB1 –94ATTG2 allele and GG allele in the 3'-untranslated region of NFKBIA were more prevalent in HCC patients than in the healthy controls. NFKBIA –826CT and NFKBIA –881AG allelic carriages were more prevalent in HCC patients than in the non-HCC subjects with HBV infection. The estimated haplotype frequency of NFKBIA promoter –881G–826T–519C was significantly higher in the patients with HCC than in the HBV-infected subjects without HCC (odds ratio = 3.142, P = 0.002). As compared with the HBV-infected subjects without HCC, NFKBIA –826 T and NFKBIA –881AG allelic carriages were only associated with HCC risk in the subjects with HBV genotype C. The association of NFKBIA –881AG allelic carriage with HCC risk was not affected by liver cirrhosis (LC) status, alanine aminotransferase level and hepatitis B e antigen status. By multivariate regression analysis, NFKB1 –94ATTG2, NFKBIA –826T, NFKBIA –881AG and HBV genotype C were independently associated with an increased risk of HCC. In conclusion, NFKB1 –94ATTG2 allele and haplotype –881G–826T–519C in NFKBIA promoter were associated with hepatocarcinogenesis. NFKBIA –826T and –881AG were associated with the risk of HCC in the subjects infected with HBV genotype C.

  S. L Park , D Bastani , B. Y Goldstein , S. C Chang , W Cozen , L Cai , C Cordon Cardo , B Ding , S Greenland , N He , S. K Hussain , Q Jiang , Y. C. A Lee , S Liu , M. L Lu , T. M Mack , J. T Mao , H Morgenstern , L. N Mu , S. S Oh , A Pantuck , J. C Papp , J Rao , V. E Reuter , D. P Tashkin , H Wang , N. C. Y You , S. Z Yu , J. K Zhao and Z. F. Zhang
 

Constituents of tobacco smoke can cause DNA double-strand breaks (DSBs), leading to tumorigenesis. The NBS1 gene product is a vital component in DSB detection and repair, thus genetic variations may influence cancer development. We examined the associations between NBS1 polymorphisms and haplotypes and newly incident smoking-related cancers in three case–control studies (Los Angeles: 611 lung and 601 upper aero-digestive tract (UADT) cancer cases and 1040 controls; Memorial Sloan-Kettering Cancer Center: 227 bladder cancer cases and 211 controls and Taixing, China: 218 esophagus, 206 stomach, 204 liver cancer cases and 415 controls). rs1061302 was associated with cancers of the lung [adjusted odds ratio (ORadj) = 1.6, 95% confidence interval (CI): 1.2, 2.4], larynx (ORadj = 0.56, 95% CI: 0.32, 0.97) and liver (ORadj = 1.7, 95% CI: 1.0, 2.9). Additionally, positive associations were found for rs709816 with bladder cancer (ORadj = 4.2, 95% CI: 1.4, 12) and rs1063054 with lung cancer (ORadj = 1.6, 95% CI: 1.0, 2.3). Some associations in lung and stomach cancers varied with smoking status. CAC haplotype was positively associated with smoking-related cancers: lung (ORadj = 1.7, 95% CI: 1.1, 2.9) and UADT (ORadj = 2.0, 95% CI: 1.1, 3.7), specifically, oropharynx (ORadj = 2.1, 95% CI: 1.0, 4.2) and larynx (ORadj = 4.8, 95% CI: 1.7, 14). Bayesian false-discovery probabilities were calculated to assess Type I error. It appears that NBS1 polymorphisms and haplotypes may be associated with smoking-related cancers and that these associations may differ by smoking status. Our findings also suggest that single-nucleotide polymorphisms located in the binding region of the MRE-RAD50-NBS1 complex or microRNA targeted pathways may influence tumor development. These hypotheses should be further examined in functional studies.

  U. A Hvidtfeldt , J. S Tolstrup , M. U Jakobsen , B. L Heitmann , M Gronbaek , E O'Reilly , K Balter , U Goldbourt , G Hallmans , P Knekt , S Liu , M Pereira , P Pietinen , D Spiegelman , J Stevens , J Virtamo , W. C Willett , E. B Rimm and A. Ascherio
 

Background— Light to moderate alcohol consumption is associated with a reduced risk of coronary heart disease. This protective effect of alcohol, however, may be confined to middle-aged or older individuals. Coronary heart disease incidence is low in men <40 years of age and in women <50 years of age; for this reason, study cohorts rarely have the power to investigate the effects of alcohol on coronary heart disease risk in younger adults. This study examined whether the beneficial effect of alcohol on coronary heart disease depends on age.

Methods and Results— In this pooled analysis of 8 prospective studies from North America and Europe including 192 067 women and 74 919 men free of cardiovascular diseases, diabetes, and cancers at baseline, average daily alcohol intake was assessed at baseline with a food frequency or diet history questionnaire. An inverse association between alcohol and risk of coronary heart disease was observed in all age groups; hazard ratios among moderately drinking men (5.0 to 29.9 g/d) 39 to 50, 50 to 59, and ≥60 years of age were 0.58 (95% confidence interval [CI], 0.36 to 0.93), 0.72 (95% CI, 0.60 to 0.86), and 0.85 (95% CI, 0.75 to 0.97) compared with abstainers. However, the analyses indicated a smaller incidence rate difference between abstainers and moderate consumers in younger adults (incidence rate difference, 45 per 100 000; 90% CI, 8 to 84) than in middle-aged (incidence rate difference, 64 per 100 000; 90% CI, 24 to 102) and older (incidence rate difference, 89 per 100 000; 90% CI, 44 to 140) adults. Similar results were observed in women.

Conclusion— Alcohol is also associated with a decreased risk of coronary heart disease in younger adults; however, the absolute risk was small compared with middle-aged and older adults.

  J Hsia , R. J Rodabough , J. E Manson , S Liu , M. S Freiberg , W Graettinger , M. C Rosal , B Cochrane , D Lloyd Jones , J. G Robinson , B. V Howard and for the Women's Health Initiative Research Group
 

Background— The 2007 update to the American Heart Association (AHA) guidelines for cardiovascular disease prevention in women recommend a simplified approach to risk stratification. We assigned Women’s Health Initiative participants to risk categories as described in the guideline and evaluated clinical event rates within and between strata.

Methods and Results— The Women’s Health Initiative enrolled 161 808 women ages 50 to 79 years and followed them prospectively for 7.8 years (mean). Applying the 2007 AHA guideline categories, 11% of women were high risk, 72% at-risk, and 4% at optimal risk; 13% of women did not fall into any category, that is, lacked risk factors but did not adhere to a healthy lifestyle (moderate intensity exercise for 30 minute most days and <7% of calories from saturated fat). Among high risk, at-risk, and optimal risk women, rates of myocardial infarction/coronary death were 12.5%, 3.1%, and 1.1% per 10 years (P for trend <0.0001); the event rate was 1.3% among women who could not be categorized. We observed a graded relationship between risk category and cardiovascular event rates for white, black, Hispanic, and Asian women, although event rates differed among ethnic groups (P for interaction=0.002). The AHA guideline predicted coronary events with accuracy similar to current Framingham risk categories (area under receiver operating characteristic curve for Framingham risk, 0.665; for AHA risk, 0.664; P=0.94) but less well than proposed Framingham 10-year risk categories of <5%, 5% to 20%, and >20% (area under receiver operating characteristic curve for Framingham risk, 0.724; for AHA risk, 0.664; P<0.0001).

Conclusions— Risk stratification as proposed in the 2007 AHA guideline is simple, accessible to patients and providers, and identifies cardiovascular risk with accuracy similar to that of the current Framingham algorithm.

Clinical Trial Registration— clinicaltrials.gov. Identifier: NCT00000611.

  J. B Wetmore , S Liu , R Krebill , R Menard and L. D. Quarles
 

Background and objectives: Fibroblast growth factor-23 (FGF23) levels are elevated in ESRD and have been associated with adverse outcomes. The effects of various treatments for secondary hyperparathyroidism on FGF23 levels in ESRD have not been examined in a clinical trial.

Design, setting, participants, & measurements: We assessed intact FGF23 levels in 91 subjects over the course of the ACHIEVE trial, which was designed to compare escalating doses of Cinacalcet plus fixed low-dose calcitriol analogs (Cinaclcet-D) with titration of calcitriol analogs alone (Flex-D) to suppress parathyroid hormone. Between-group and within-group changes in log-transformed FGF23 levels were analyzed. Factors associated with change in FGF23 were assessed using a multiple regression model.

Results: Intact FGF23 levels were markedly elevated in subjects at baseline. A statistically significant difference in percent change in log FGF23 levels was observed between treatment groups (P < 0.002). The Cinacalcet-D group had a significant decrease in percent change in log FGF23 levels (corrected P = 0.021), whereas FGF23 levels trended toward an increase in the Flex-D group. Change in FGF23 level was significantly associated with changes in levels of phosphate (P < 0.0001) and calcium (P = 0.0002) but not parathyroid hormone.

Conclusions: Treatment with Cinacalcet plus low-dose calcitriol analogs results in lower FGF23 levels compared with a treatment regimen using calcitriol analogs alone in ESRD. The mechanisms underlying the differential effects of these treatment regimens on FGF23 levels and the clinical impact of these changes on FGF23 remain to be defined.

  M. A Horner , K Pardee , S Liu , K King Jones , G Lajoie , A Edwards , H. M Krause and C. S. Thummel
 

Cholesterol homeostasis is required to maintain normal cellular function and avoid the deleterious effects of hypercholesterolemia. Here we show that the Drosophila DHR96 nuclear receptor binds cholesterol and is required for the coordinate transcriptional response of genes that are regulated by cholesterol and involved in cholesterol uptake, trafficking, and storage. DHR96 mutants die when grown on low levels of cholesterol and accumulate excess cholesterol when maintained on a high-cholesterol diet. The cholesterol accumulation phenotype can be attributed to misregulation of npc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietary cholesterol uptake. These studies define DHR96 as a central regulator of cholesterol homeostasis.

  S Liu , H Zhang , C Gu , J Yin , Y He , J Xie and G. Cao
  Background

The association between hepatitis B virus (HBV) mutations and hepatocarcinogenesis remains controversial because of conflicting data in the literature. We conducted a meta-analysis of case–control and cohort studies to examine HBV PreS, enhancer II (EnhII), basal core promoter (BCP), and precore mutations in relation to the risk of hepatocellular carcinoma (HCC).

Methods

We searched databases for studies of these associations that were published in English or Chinese up to August 31, 2008. HBV mutation–specific odds ratios and relative risks were pooled by use of a random-effects model and stratified by potential confounders. All statistical tests were two-sided.

Results

Of the 43 studies included in this meta-analysis, 40 used a case–control design. The 43 studies evaluated a total of 11 582 HBV-infected participants, of whom 2801 had HCC. Statistically significant summary odds ratios of HCC were obtained for any PreS mutation (3.77, 95% confidence interval [CI] = 2.57 to 5.52), C1653T in EnhII (2.76, 95% CI = 2.09 to 3.64), T1753V (2.35, 95% CI = 1.63 to 3.40), and A1762T/G1764A in BCP (3.79, 95% CI = 2.71 to 5.29). PreS mutations were more strongly associated with an increased risk of HCC in subjects who were infected with HBV genotype C than in those who were infected with HBV genotype B, whereas the opposite was true for A1762T/G1764A. C1653T, T1753V, and A1762T/G1764A were more strongly associated with an increased risk of HCC in hepatitis B e antigen (HBeAg)–positive subjects than in HBeAg-negative subjects. PreS mutations, C1653T, T1753V, and A1762T/G1764A accumulated during the progression of chronic HBV infection from the asymptomatic carrier state to HCC (Ptrend < .001 for each mutation). PreS mutations, C1653T, C1653T + T1753V, and A1762T/G1764A-based combinations of mutations had specificities greater than 80% for the prediction of HCC. The precore mutations G1896A and C1858T were not associated with the risk of HCC, regardless of HBeAg status and HBV genotype.

Conclusions

HBV PreS mutations, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. These mutations alone and in combination may be predictive for hepatocarcinogenesis.

  S Liu , W Tang , J Fang , J Ren , H Li , Z Xiao and L. D. Quarles
 

We used gene array analysis of cortical bone to identify Phex-dependent gene transcripts associated with abnormal Fgf23 production and mineralization in Hyp mice. We found evidence that elevation of Fgf23 expression in osteocytes is associated with increments in Fgf1, Fgf7, and Egr2 and decrements in Sost, an inhibitor in the Wnt-signaling pathway, were observed in Hyp bone. β-Catenin levels were increased in Hyp cortical bone, and TOPflash luciferase reporter assay showed increased transcriptional activity in Hyp-derived osteoblasts, consistent with Wnt activation. Moreover, activation of Fgf and Wnt-signaling stimulated Fgf23 promoter activity in osteoblasts. We also observed reductions in Bmp1, a metalloproteinase that metabolizes the extracellular matrix protein Dmp1. Alterations were also found in enzymes regulating the posttranslational processing and stability of Fgf23, including decrements in the glycosyltransferase Galnt3 and the proprotein convertase Pcsk5. In addition, we found that the Pcsk5 and the glycosyltransferase Galnt3 were decreased in Hyp bone, suggesting that reduced posttranslational processing of FGF23 may also contribute to increased Fgf23 levels in Hyp mice. With regard to mineralization, we identified additional candidates to explain the intrinsic mineralization defect in Hyp osteoblasts, including increases in the mineralization inhibitors Mgp and Thbs4, as well as increases in local pH-altering factors, carbonic anhydrase 12 (Car12) and 3 (Car3) and the sodium-dependent citrate transporter (Slc13a5). These studies demonstrate the complexity of gene expression alterations in bone that accompanies inactivating Phex mutations and identify novel pathways that may coordinate Fgf23 expression and mineralization of extracellular matrix in Hyp bone.

  F Li , D. Y Hu , S Liu , S Mahavadi , W Yen , K. S Murthy , K Khalili and W. Hu
 

Regulator of G protein signaling 4 (RGS4) regulates the strength and duration of G protein signaling and plays an important role in smooth muscle contraction, cardiac development, and psychiatric disorders. Little is known about the posttranscriptional regulation of RGS4 expression. We cloned the full-length cDNA of rabbit RGS4, which contains a long 3'-untranslated region (UTR) with several AU-rich elements (AREs). We determined whether RGS4 mRNA stability is mediated by the RNA-binding protein human antigen R (HuR) and contributes to IL-1β-induced upregulation of RGS4 expression. We show that IL-1β treatment in colonic smooth muscle cells doubled the half-life of RGS4 mRNA. Addition of RGS4 3'-UTR to the downstream of Renilla luciferase reporter induced dramatic reduction in the enzyme activity and mRNA expression of luciferase, which was attenuated by the site-directed mutation of the two 3'-most ARE sites. IL-1β increased luciferase mRNA stability in a UTR-dependent manner. Knockdown of HuR significantly aggravated UTR-mediated instability of luciferase and inhibited IL-1β-induced upregulation of RGS4 mRNA. In addition, IL-1β increased cytosolic translocation and RGS4 mRNA binding of HuR. These findings suggest that 3'-most ARE sites within RGS4 3'-UTR are essential for the instability of RGS4 mRNA and IL-1β promotes the stability of RGS4 mRNA through HuR.

  H Dong , K. N Shim , J. M. J Li , C Estrema , T. A Ornelas , F Nguyen , S Liu , S. L Ramamoorthy , S Ho , J. M Carethers and J. Y. C. Chow
 

We recently reported that transforming growth factor-β (TGF-β) induces an increase in cytosolic Ca2+ ([Ca2+]cyt) in pancreatic cancer cells, but the mechanisms by which TGF-β mediates [Ca2+]cyt homeostasis in these cells are currently unknown. Transient receptor potential (TRP) channels and Na+/Ca2+ exchangers (NCX) are plasma membrane proteins that play prominent roles in controlling [Ca2+]cyt homeostasis in normal mammalian cells, but little is known regarding their roles in the regulation of [Ca2+]cyt in pancreatic cancer cells and pancreatic cancer development. Expression and function of NCX1 and TRPC1 proteins were characterized in BxPc3 pancreatic cancer cells. TGF-β induced both intracellular Ca2+ release and extracellular Ca2+ entry in these cells; however, 2-aminoethoxydiphenyl borate [2-APB; a blocker for both inositol 1,4,5-trisphosphate (IP3) receptor and TRPC], LaCl3 (a selective TRPC blocker), or KB-R7943 (a selective inhibitor for the Ca2+ entry mode of NCX) markedly inhibited the TGF-β-induced increase in [Ca2+]cyt. 2-APB or KB-R7943 treatment was able to dose-dependently reverse membrane translocation of PKC induced by TGF-β. Transfection with small interfering RNA (siRNA) against NCX1 almost completely abolished NCX1 expression in BxPc3 cells and also inhibited PKC serine phosphorylation induced by TGF-β. Knockdown of NCX1 or TRPC1 by specific siRNA transfection reversed TGF-β-induced pancreatic cancer cell motility. Therefore, TGF-β induces Ca2+ entry likely via TRPC1 and NCX1 and raises [Ca2+]cyt in pancreatic cancer cells, which is essential for PKC activation and subsequent tumor cell invasion. Our data suggest that TRPC1 and NCX1 may be among the potential therapeutic targets for pancreatic cancer.

 
 
 
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